Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Protein kinase C, an elusive therapeutic target?

Key Points

  • The protein kinase C (PKC) family comprises a group of highly related enzymes that phosphorylate serine and threonine residues on a large number of proteins.

  • Increased activation of specific PKC isozymes has been observed in numerous diseases and indications, including cancer, heart failure, myocardial infarction, stroke, neurodegenerative diseases, autoimmune conditions and psychiatric disorders.

  • Individual members of the PKC family have diverse and sometimes opposing roles.

  • As PKC isozymes are ubiquitously expressed, isozyme-specific modulators are highly desirable for treating particular diseases.

  • Efforts to develop selective small-molecule inhibitors targeting the ATP-binding site and the diacylglycerol-binding site have been challenging because of the high degree of homology among the PKC isozymes.

  • Peptide inhibitors of protein–protein interactions — between individual PKC isozymes and their anchoring proteins and/or substrates — appear to have improved selectivity.

  • Results of clinical trials of PKC modulators have been modest at best.

  • Although no specific PKC modulators have yet received regulatory approval, PKC isozymes remain important targets for many unmet clinical needs.

  • Some of the challenges associated with the preclinical research and the clinical studies are discussed in this Review.

Abstract

Protein kinase C (PKC) has been a tantalizing target for drug discovery ever since it was first identified as the receptor for the tumour promoter phorbol ester in 1982. Although initial therapeutic efforts focused on cancer, additional indications — including diabetic complications, heart failure, myocardial infarction, pain and bipolar disorder — were targeted as researchers developed a better understanding of the roles of eight conventional and novel PKC isozymes in health and disease. Unfortunately, both academic and pharmaceutical efforts have yet to result in the approval of a single new drug that specifically targets PKC. Why does PKC remain an elusive drug target? This Review provides a short account of some of the efforts, challenges and opportunities in developing PKC modulators to address unmet clinical needs.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Domain composition of PKC family members shown in a stick representation.
Figure 2: Processes leading to dissociation of the intramolecular inhibitory interaction in PKC and to activation of the enzyme.
Figure 3: Role of PKC isozymes in ischaemic heart disease.
Figure 4: Inhibitors of PKC.

Similar content being viewed by others

References

  1. Castagna, M. et al. Direct activation of calcium-activated, phospholipid-dependent protein-kinase by tumor-promoting phorbo esters. J. Biol. Chem. 257, 7847–7851 (1982). This is the first study that suggested a pathological role for PKC in cancer and triggered active research in the scientific community.

    CAS  PubMed  Google Scholar 

  2. Geraldes, P. & King, G. L. Activation of protein kinase C isoforms and its impact on diabetic complications. Circ. Res. 106, 1319–1331 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Toton, E., Ignatowicz, E., Skrzeczkowska, K. & Rybczynska, M. Protein kinase Cɛ as a cancer marker and target for anticancer therapy. Pharmacol. Rep. 63, 19–29 (2011).

    CAS  PubMed  Google Scholar 

  4. Inagaki, K., Churchill, E. & Mochly-Rosen, D. Epsilon protein kinase C as a potential therapeutic target for the ischemic heart. Cardiovasc. Res. 70, 222–230 (2006).

    CAS  PubMed  Google Scholar 

  5. Ferreira, J. C., Brum, P. C. & Mochly-Rosen, D. βIIPKC and ɛPKC isozymes as potential pharmacological targets in cardiac hypertrophy and heart failure. J. Mol. Cell. Cardiol. 51, 479–484 (2011).

    CAS  PubMed  Google Scholar 

  6. Zanin-Zhorov, A., Dustin, M. L. & Blazar, B. R. PKC-θ function at the immunological synapse: prospects for therapeutic targeting. Trends Immunol. 32, 358–363 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Burguillos, M. A. et al. Caspase signalling controls microglia activation and neurotoxicity. Nature 472, 319–324 (2011).

    CAS  PubMed  Google Scholar 

  8. Zhang, D., Anantharam, V., Kanthasamy, A. & Kanthasamy, A. G. Neuroprotective effect of protein kinase Cδ inhibitor rottlerin in cell culture and animal models of Parkinson's disease. J. Pharmacol. Exp. Ther. 322, 913–922 (2007).

    CAS  PubMed  Google Scholar 

  9. Garrido, J. L., Godoy, J. A., Alvarez, A., Bronfman, M. & Inestrosa, N. C. Protein kinase C inhibits amyloid β peptide neurotoxicity by acting on members of the Wnt pathway. FASEB J. 16, 1982–1984 (2002).

    CAS  PubMed  Google Scholar 

  10. Manji, H. K. & Lenox, R. H. The nature of bipolar disorder. J. Clin. Psychiatry 61 (Suppl. 13), 42–57 (2000).

    PubMed  Google Scholar 

  11. Zarate, C. A. & Manji, H. K. Protein kinase C inhibitors: rationale for use and potential in the treatment of bipolar disorder. CNS Drugs 23, 569–582 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Maioli, E. & Valacchi, G. Rottlerin: bases for a possible usage in psoriasis. Curr. Drug Metab. 11, 425–430 (2010).

    CAS  PubMed  Google Scholar 

  13. Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912–1934 (2002). This is a detailed analysis of kinase inhibitors of the ATP-binding site across the kinome, and it provides effective visual illustrations for the lack of specificity of the inhibitors for specific protein kinases.

    CAS  PubMed  Google Scholar 

  14. Takai, Y., Kishimoto, A., Inoue, M. & Nishizuka, Y. Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. 1. Purification and characterization of an active enzyme from bovine cerebellum. J. Biol. Chem. 252, 7603–7609 (1977). This is the first description of PKC activity by Nishizuka's laboratory.

    CAS  PubMed  Google Scholar 

  15. Takai, Y., Kishimoto, A., Kikkawa, U., Mori, T. & Nishizuka, Y. Unsaturated diacylglycerol as a possible messenger for the activation of calcium-activated, phospholipid dependent protein-kinase system. Biochem. Biophys. Res. Commun. 91, 1218–1224 (1979).

    CAS  PubMed  Google Scholar 

  16. Coussens, L. et al. Multiple, distinct forms of bovin and human protein-kinase-C suggest diversity in cellular signaling pathway. Science 233, 859–866 (1986).

    CAS  PubMed  Google Scholar 

  17. Ono, Y. et al. The structure, expression, and properties of additional members of the protein kinase C family. J. Biol. Chem. 263, 6927–6932 (1988).

    CAS  PubMed  Google Scholar 

  18. Ono, Y. et al. Expression and properties of two types of protein kinase C: alternative splicing from a single gene. Science 236, 1116–1120 (1987).

    CAS  PubMed  Google Scholar 

  19. Parker, P. J. et al. The complete primary structure of protein-kinase C — the phorbol ester receptor. Science 233, 853–859 (1986).

    CAS  PubMed  Google Scholar 

  20. Hirai, T. & Chida, K. Protein kinase Cζ (PKCζ): activation mechanisms and cellular functions. J. Biochem. 133, 1–7 (2003).

    CAS  PubMed  Google Scholar 

  21. Suzuki, A., Akimoto, K. & Ohno, S. Protein kinase Cλ/ι (PKCλ/ι): a PKC isotype essential for the development of multicellular organisms. J. Biochem. 133, 9–16 (2003).

    CAS  PubMed  Google Scholar 

  22. Steinberg, S. F. Structural basis of protein kinase C isoform function. Physiol. Rev. 88, 1341–1378 (2008).

    CAS  PubMed  Google Scholar 

  23. Persaud, S. D., Hoang, V., Huang, J. & Basu, A. Involvement of proteolytic activation of PKCδ in cisplatin-induced apoptosis in human small cell lung cancer H69 cells. Int. J. Oncol. 27, 149–154 (2005).

    CAS  PubMed  Google Scholar 

  24. Newton, A. C. Protein kinase C: structure, function, and regulation. J. Biol. Chem. 270, 28495–28498 (1995). This is a review of the family of PKC isozymes.

    CAS  PubMed  Google Scholar 

  25. Konishi, H. et al. Activation of protein kinase C by tyrosine phosphorylation in response to H2O2 . Proc. Natl Acad. Sci. USA 94, 11233–11237 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Konishi, H. et al. Phosphorylation sites of protein kinase Cδ in H2O2-treated cells and its activation by tyrosine kinase in vitro. Proc. Natl Acad. Sci. USA 98, 6587–6592 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Mochly-Rosen, D. Localization of protein kinases by anchoring proteins: a theme in signal transduction. Science 268, 247–251 (1995).

    CAS  PubMed  Google Scholar 

  28. Chen, L. et al. Opposing cardioprotective actions and parallel hypertrophic effects of δPKC and ɛPKC. Proc. Natl Acad. Sci. USA 98, 11114–11119 (2001). This paper provides the first evidence that the same PKC isozymes may have opposing roles.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Murriel, C. L. & Mochly-Rosen, D. Opposing roles of δ and ɛ PKC in cardiac ischemia and reperfusion: targeting the apoptotic machinery. Arch. Biochem. Biophys. 420, 246–254 (2003).

    CAS  PubMed  Google Scholar 

  30. Basu, A. & Pal, D. Two faces of protein kinase Cδ: the contrasting roles of PKCδ in cell survival and cell death. ScientificWorldJournal 10, 2272–2284 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Michie, A. M. & Nakagawa, R. The link between PKCα regulation and cellular transformation. Immunol. Lett. 96, 155–162 (2005).

    CAS  PubMed  Google Scholar 

  32. Ishii, H. et al. Amelioration of vascular dysfunctions in diabetic rats by an oral PKCβ inhibitor. Science 272, 728–731 (1996).

    CAS  PubMed  Google Scholar 

  33. Simonis, G., Braun, M. U., Kirrstetter, M., Schon, S. P. & Strasser, R. H. Mechanisms of myocardial remodeling: ramiprilat blocks the expressional upregulation of protein kinase C-ɛ in the surviving myocardium early after infarction. J. Cardiovasc. Pharmacol. 41, 780–787 (2003).

    CAS  PubMed  Google Scholar 

  34. Bowling, N. et al. Increased protein kinase C activity and expression of Ca2+-sensitive isoforms in the failing human heart. Circulation 99, 384–391 (1999).

    CAS  PubMed  Google Scholar 

  35. Palaniyandi, S. S., Sun, L., Ferreira, J. C. & Mochly-Rosen, D. Protein kinase C in heart failure: a therapeutic target? Cardiovasc. Res. 82, 229–239 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Koyanagi, T. et al. Pharmacological inhibition of epsilon PKC suppresses chronic inflammation in murine cardiac transplantation model. J. Mol. Cell. Cardiol. 43, 517–522 (2007).

    CAS  PubMed  Google Scholar 

  37. Dempsey, E. C., Cool, C. D. & Littler, C. M. Lung disease and PKCs. Pharmacol. Res. 55, 545–559 (2007).

    CAS  PubMed  Google Scholar 

  38. Li, J. & Gobe, G. Protein kinase C activation and its role in kidney disease. Nephrology 11, 428–434 (2006).

    CAS  PubMed  Google Scholar 

  39. Tuttle, K. R. Protein kinase C-β inhibition for diabetic kidney disease. Diabetes Res. Clin. Pract. 82 (Suppl. 1), 70–74 (2008).

    Google Scholar 

  40. Varin, M. M. et al. In Sjogren's syndrome, B lymphocytes induce epithelial cells of salivary glands into apoptosis through protein kinase Cδ activation. Autoimmun. Rev. 11, 252–258 (2012).

    CAS  PubMed  Google Scholar 

  41. Bright, R. & Mochly-Rosen, D. The role of protein kinase C in cerebral ischemic and reperfusion injury. Stroke 36, 2781–2790 (2005).

    CAS  PubMed  Google Scholar 

  42. Sun, M.-K. & Alkon, D. L. Pharmacology of protein kinase C activators: cognition-enhancing and antidementic therapeutics. Pharmacol. Therap. 127, 66–77 (2010).

    CAS  Google Scholar 

  43. Alkon, D. L., Sun, M. K. & Nelson, T. J. PKC signaling deficits: a mechanistic hypothesis for the origins of Alzheimer's disease. Trends Pharmacol. Sci. 28, 51–60 (2007).

    CAS  PubMed  Google Scholar 

  44. Sweitzer, S. M. et al. Protein kinase Cɛ and γ: involvement in formalin-induced nociception in neonatal rats. J. Pharmacol. Exp. Ther. 309, 616–625 (2004).

    CAS  PubMed  Google Scholar 

  45. Ytrehus, K., Liu, Y. & Downey, J. M. Preconditioning protects ischemic rabbit heart by protein kinase C activation. Am. J. Physiol. 266, H1145–H1152 (1994).

    CAS  PubMed  Google Scholar 

  46. Brooks, G. & Hearse, D. J. Role of protein kinase C in ischemic preconditioning: player or spectator? Circ. Res. 79, 627–630 (1996).

    CAS  PubMed  Google Scholar 

  47. Churchill, E. N., Murriel, C. L., Chen, C. H., Mochly-Rosen, D. & Szweda, L. I. Reperfusion-induced translocation of δPKC to cardiac mitochondria prevents pyruvate dehydrogenase reactivation. Circ. Res. 97, 78–85 (2005).

    CAS  PubMed  Google Scholar 

  48. Churchill, E. N., Ferreira, J. C., Brum, P. C., Szweda, L. I. & Mochly-Rosen, D. Ischaemic preconditioning improves proteasomal activity and increases the degradation of δPKC during reperfusion. Cardiovasc. Res. 85, 385–394 (2010).

    CAS  PubMed  Google Scholar 

  49. Pratschke, J., Weiss, S., Neuhaus, P. & Pascher, A. Review of nonimmunological causes for deteriorated graft function and graft loss after transplantation. Transpl. Int. 21, 512–522 (2008).

    PubMed  Google Scholar 

  50. Tanaka, M. et al. Suppression of graft coronary artery disease by a brief treatment with a selective ɛPKC activator and a δPKC inhibitor in murine cardiac allografts. Circulation 110 (Suppl. II), 194–199 (2004).

    Google Scholar 

  51. Sarma, N. J., Tiriveedhi, V., Angaswamy, N. & Mohanakumar, T. Role of antibodies to self-antigens in chronic allograft rejection: potential mechanism and therapeutic implications. Hum. Immunol. 9 Jul 2012 [epub ahead of print].

  52. Inagaki, K., Hahn, H. S., Dorn, G. W. & Mochly-Rosen, D. Additive protection of the ischemic heart ex vivo by combined treatment with δ-protein kinase C inhibitor and ɛ-protein kinase C activator. Circulation 108, 869–875 (2003).

    CAS  PubMed  Google Scholar 

  53. Lee, M. R., Duan, W. & Tan, S. L. Protein kinase C isozymes as potential therapeutic targets in immune disorders. Expert Opin. Ther. Targets 12, 535–552 (2008).

    CAS  PubMed  Google Scholar 

  54. Sledge, G. W. Jr & Gokmen-Polar, Y. Protein kinase C-β as a therapeutic target in breast cancer. Semin. Oncol. 33, S15–S18 (2006).

    CAS  PubMed  Google Scholar 

  55. Kim, J., Koyanagi, T. & Mochly-Rosen, D. PKCδ activation mediates angiogenesis via NADPH oxidase activity in PC-3 prostate cancer cells. Prostate 71, 946–954 (2011).

    CAS  PubMed  Google Scholar 

  56. Bacher, N., Zisman, Y., Berent, E. & Livneh, E. Isolation and characterization of PKC-L, a new member of the protein kinase C-related gene family specifically expressed in lung, skin, and heart. Mol. Cell. Biol. 11, 126–133 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Krasnitsky, E. et al. PKCη is a novel prognostic marker in non-small cell lung cancer. Anticancer Res. 32, 1507–1513 (2012).

    PubMed  Google Scholar 

  58. Kim, K. M. et al. PKCθ expression in gastrointestinal stromal tumor. Mod. Pathol. 19, 1480–1486 (2006).

    CAS  PubMed  Google Scholar 

  59. Nishikawa, T., Edelstein, D. & Brownlee, M. The missing link: a single unifying mechanism for diabetic complications. Kidney Int. Suppl. 77, S26–S30 (2000).

    CAS  PubMed  Google Scholar 

  60. Bezy, O. et al. PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans. J. Clin. Invest. 121, 2504–2517 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Manji, H. K. et al. Modulation of CNS signal transduction pathways and gene expression by mood-stabilizing agents: therapeutic implications. J. Clin. Psychiatry 60 (Suppl. 2), 27–39; discussion 40–41, 113–116 (1999).

    PubMed  Google Scholar 

  62. DiazGranados, N. & Zarate, C. A. Jr. A review of the preclinical and clinical evidence for protein kinase C as a target for drug development for bipolar disorder. Curr. Psychiatry Rep. 10, 510–519 (2008).

    PubMed  PubMed Central  Google Scholar 

  63. Einat, H., Yuan, P., Szabo, S. T., Dogra, S. & Manji, H. K. Protein kinase C inhibition by tamoxifen antagonizes manic-like behavior in rats: implications for the development of novel therapeutics for bipolar disorder. Neuropsychobiology 55, 123–131 (2007).

    CAS  PubMed  Google Scholar 

  64. Wang, H. Y., Markowitz, P., Levinson, D., Undie, A. S. & Friedman, E. Increased membrane-associated protein kinase C activity and translocation in blood platelets from bipolar affective disorder patients. J. Psychiatr. Res. 33, 171–179 (1999).

    CAS  PubMed  Google Scholar 

  65. Wang, H. Y. & Friedman, E. Enhanced protein kinase C activity and translocation in bipolar affective disorder brains. Biol. Psychiatry 40, 568–575 (1996).

    CAS  PubMed  Google Scholar 

  66. Sadeh, J. S. et al. Pustular and erythrodermic psoriasis complicated by acute respiratory distress syndrome. Arch. Dermatol. 133, 747–750 (1997).

    CAS  PubMed  Google Scholar 

  67. Nishino, N., Kitamura, N., Hashimoto, T. & Tanaka, C. Transmembrane signalling systems in the brain of patients with Parkinson's disease. Rev. Neurosci. 4, 213–222 (1993).

    CAS  PubMed  Google Scholar 

  68. Karaman, M. W. et al. A quantitative analysis of kinase inhibitor selectivity. Nature Biotech. 26, 127–132 (2008).

    CAS  Google Scholar 

  69. Sobhia, M. E., Grewal, B. K., Bhat, J., Rohit, S. & Punia, V. Protein kinase CβII in diabetic complications: survey of structural, biological and computational studies. Expert Opin. Ther. Targets 16, 325–344 (2012).

    CAS  PubMed  Google Scholar 

  70. Wilkinson, S. E., Parker, P. J. & Nixon, J. S. Isoenzyme specificity of bisindolylmaleimides, selective inhibitors of protein kinase C. Biochem. J. 294, 335–337 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Lee, K. W. et al. Enzastaurin, a protein kinase Cβ inhibitor, suppresses signaling through the ribosomal S6 kinase and bad pathways and induces apoptosis in human gastric cancer cells. Cancer Res. 68, 1916–1926 (2008).

    CAS  PubMed  Google Scholar 

  72. Gschwendt, M. et al. Rottlerin, a novel protein-kinase inhibitor. Biochem. Biophys. Res. Commun. 199, 93–98 (1994).

    CAS  PubMed  Google Scholar 

  73. Soltoff, S. P. Rottlerin: an inappropriate and ineffective inhibitor of PKCδ. Trends Pharmacol. Sci. 28, 453–458 (2007).

    CAS  PubMed  Google Scholar 

  74. Zimmermann, J. et al. Phenylamino-pyrimidine (PAP) derivatives: a new class of potent and selective inhibitors of protein kinase C (PKC). Arch. Pharm. 329, 371–376 (1996).

    CAS  Google Scholar 

  75. Cole, D. C. et al. Identification, characterization and initial hit-to-lead optimization of a series of 4-arylamino-3-pyridinecarbonitrile as protein kinase Cθ (PKCθ) inhibitors. J. Med. Chem. 51, 5958–5963 (2008).

    CAS  PubMed  Google Scholar 

  76. Pande, V., Ramos, M. J. & Gago, F. The protein kinase inhibitor balanol: structure–activity relationships and structure-based computational studies. Anticancer Agents Med. Chem. 8, 638–645 (2008).

    CAS  PubMed  Google Scholar 

  77. Noh, K. M., Hwang, J. Y., Shin, H. C. & Koh, J. Y. A novel neuroprotective mechanism of riluzole: direct inhibition of protein kinase C. Neurobiol. Dis. 7, 375–383 (2000).

    CAS  PubMed  Google Scholar 

  78. Blumberg, P. M. In vitro studies on the mode of action of the phorbol esters, potent tumor promoters: part 1. Crit. Rev. Toxicol. 8, 153–197 (1980). This is one of the early studies that elucidated the pharmacology of phorbol esters.

    CAS  PubMed  Google Scholar 

  79. Blumberg, P. M. et al. Mechanism of action of the phorbol ester tumor promoters: specific receptors for lipophilic ligands. Biochem. Pharmacol. 33, 933–940 (1984).

    CAS  PubMed  Google Scholar 

  80. Marquez, V. E. et al. The transition from a pharmacophore-guided approach to a receptor-guided approach in the design of potent protein kinase C ligands. Pharmacol. Ther. 82, 251–261 (1999).

    CAS  PubMed  Google Scholar 

  81. Garcia-Bermejo, M. L. et al. Diacylglycerol (DAG)-lactones, a new class of protein kinase C (PKC) agonists, induce apoptosis in LNCaP prostate cancer cells by selective activation of PKCα. J. Biol. Chem. 277, 645–655 (2002).

    CAS  PubMed  Google Scholar 

  82. Workman, P., Kaye, S. B. & Schwartsmann, G. Laboratory and phase I studies of new cancer drugs. Curr. Opin. Oncol. 4, 1065–1072 (1992).

    CAS  PubMed  Google Scholar 

  83. Dowlati, A. et al. Phase I and correlative study of combination bryostatin 1 and vincristine in relapsed B-cell malignancies. Clin. Cancer Res. 9, 5929–5935 (2003).

    CAS  PubMed  Google Scholar 

  84. Szallasi, Z. et al. Bryostatin 1 protects protein kinase C-δ from down-regulation in mouse keratinocytes in parallel with its inhibition of phorbol ester-induced differentiation. Mol. Pharmacol. 46, 840–850 (1994).

    CAS  PubMed  Google Scholar 

  85. Wender, P. A., Verma, V. A., Paxton, T. J. & Pillow, T. H. Function-oriented synthesis, step economy, and drug design. Accounts Chem. Res. 41, 40–49 (2008).

    CAS  Google Scholar 

  86. Shindo, M. et al. Toward the identification of selective modulators of protein kinase C (PKC) isozymes: establishment of a binding assay for PKC isozymes using synthetic C1 peptide receptors and identification of the critical residues involved in the phorbol ester binding. Bioorg. Med. Chem. 9, 2073–2081 (2001).

    CAS  PubMed  Google Scholar 

  87. Wender, P. A. et al. Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity. Proc. Natl Acad. Sci. USA 108, 6721–6726 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Wender, P. A. et al. Inspirations from nature. New reactions, therapeutic leads, and drug delivery systems. Pure Appl. Chem. 75, 143–155 (2003).

    CAS  Google Scholar 

  89. Kraft, A. S., Anderson, W. B., Cooper, H. L. & Sando, J. J. Decrease in cytosolic calcium phospholipid-dependent protein-kinase activity following phorbol ester treatment of EL4 thymoma cells. J. Biol. Chem. 257, 3193–3196 (1982).

    Google Scholar 

  90. Disatnik, M. H., Buraggi, G. & Mochly-Rosen, D. Localization of protein kinase C isozymes in cardiac myocytes. Exp. Cell Res. 210, 287–297 (1994).

    CAS  PubMed  Google Scholar 

  91. Mochly-Rosen, D., Henrich, C. J., Cheever, L., Khaner, H. & Simpson, P. C. A protein kinase C isozyme is translocated to cytoskeletal elements on activation. Cell Regul. 1, 693–706 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Budas, G. R., Churchill, E. N., Disatnik, M. H., Sun, L. & Mochly-Rosen, D. Mitochondrial import of PKCɛ is mediated by HSP90: a role in cardioprotection from ischaemia and reperfusion injury. Cardiovasc. Res. 88, 83–92 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Goodnight, J. A., Mischak, H., Kolch, W. & Mushinski, J. F. Immunocytochemical localization of eight protein kinase C isozymes overexpressed in NIH 3T3 fibroblasts. Isoform-specific association with microfilaments, Golgi, endoplasmic reticulum, and nuclear and cell membranes. J. Biol. Chem. 270, 9991–10001 (1995).

    CAS  PubMed  Google Scholar 

  94. Kim, J. et al. Centrosomal PKCβII and pericentrin are critical for human prostate cancer growth and angiogenesis. Cancer Res. 68, 6831–6839 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Passalacqua, M., Patrone, M., Sparatore, B., Melloni, E. & Pontremoli, S. Protein kinase C-θ is specifically localized on centrosomes and kinetochores in mitotic cells. Biochem. J. 337, 113–118 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Passalacqua, M. et al. Protein kinase C-θ is specifically activated in murine erythroleukaemia cells during mitosis. FEBS Lett. 453, 249–253 (1999).

    CAS  PubMed  Google Scholar 

  97. Mochly-Rosen, D., Khaner, H. & Lopez, J. Identification of intracellular receptor proteins for activated protein kinase C. Proc. Natl Acad. Sci. USA 88, 3997–4000 (1991). This is the first study to describe RACKs as a means of anchoring activated PKC isozymes to proteins rather than only to lipids.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Hyatt, S. L., Liao, L., Chapline, C. & Jaken, S. Identification and characterization of α-protein kinase C binding proteins in normal and transformed REF52 cells. Biochemistry 33, 1223–1228 (1994).

    CAS  PubMed  Google Scholar 

  99. Kheifets, V. & Mochly-Rosen, D. Insight into intra- and inter-molecular interactions of PKC: design of specific modulators of kinase function. Pharmacol. Res. 55, 467–476 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Ron, D. et al. Cloning of an intracellular receptor for protein kinase C: a homolog of the β subunit of G proteins. Proc. Natl Acad. Sci. USA 91, 839–843 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Coussens, L., Rhee, L., Parker, P. J. & Ullrich, A. Alternative splicing increases the diversity of the human protein-kinase C family. DNA 6, 389–394 (1987).

    CAS  PubMed  Google Scholar 

  102. Adwan, T. S., Ohm, A. M., Jones, D. N. M., Humphries, M. J. & Reyland, M. E. Regulated binding of importin-α to protein kinase Cδ in response to apoptotic signals facilitates nuclear import. J. Biol. Chem. 286, 35716–35724 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Zinzalla, G. & Thurston, D. E. Targeting protein–protein interactions for therapeutic intervention: a challenge for the future. Future Med. Chem. 1, 65–93 (2009).

    CAS  PubMed  Google Scholar 

  104. Souroujon, M. C. & Mochly-Rosen, D. Peptide modulators of protein–protein interactions in intracellular signaling. Nature Biotech. 16, 919–924 (1998). This is a review describing how peptide inhibitors of protein–protein interactions can be rationally designed.

    CAS  Google Scholar 

  105. Churchill, E. N., Qvit, N. & Mochly-Rosen, D. Rationally designed peptide regulators of protein kinase C. Trends Endocrinol. Metab. 20, 25–33 (2009).

    CAS  PubMed  Google Scholar 

  106. Qvit, N. & Mochly-Rosen, D. Highly specific modulators of protein kinase C localization: applications to heart failure. Drug Discov. Today Dis. Mech. 7, e87–e93 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Prekeris, R., Mayhew, M. W., Cooper, J. B. & Terrian, D. M. Identification and localization of an actin-binding motif that is unique to the epsilon isoform of protein kinase C and participates in the regulation of synaptic function. J. Cell Biol. 132, 77–90 (1996).

    CAS  PubMed  Google Scholar 

  108. Stebbins, E. G. & Mochly-Rosen, D. Binding specificity for RACK1 resides in the V5 region of βII protein kinase C. J. Biol. Chem. 276, 29644–29650 (2001).

    CAS  PubMed  Google Scholar 

  109. Ferreira, J. C. et al. Pharmacological inhibition of βIIPKC is cardioprotective in late-stage hypertrophy. J. Mol. Cell. Cardiol. 51, 980–987 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Caino, M. C., Lopez-Haber, C., Kim, J., Mochly-Rosen, D. & Kazanietz, M. G. Protein kinase Cɛ is required for non-small cell lung carcinoma growth and regulates the expression of apoptotic genes. Oncogene 31, 2593–2600 (2012).

    CAS  PubMed  Google Scholar 

  111. Friedman, E., Hoau Yan, W., Levinson, D., Connell, T. A. & Singh, H. Altered platelet protein kinase C activity in bipolar affective disorder, manic episode. Biol. Psychiatry 33, 520–525 (1993).

    CAS  PubMed  Google Scholar 

  112. Hahn, C. G. & Friedman, E. Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disorder. Bipolar Disord. 1, 81–86 (1999).

    CAS  PubMed  Google Scholar 

  113. Podar, K., Raab, M. S., Chauhan, D. & Anderson, K. C. The therapeutic role of targeting protein kinase C in solid and hematologic malignancies. Expert Opin. Investig. Drugs 16, 1693–1707 (2007).

    CAS  PubMed  Google Scholar 

  114. Ali, A. S., Ali, S., El-Rayes, B. F., Philip, P. A. & Sarkar, F. H. Exploitation of protein kinase C: a useful target for cancer therapy. Cancer Treat. Rev. 35, 1–8 (2009).

    CAS  PubMed  Google Scholar 

  115. Reyland, M. E. Protein kinase C isoforms: multi-functional regulators of cell life and death. Front. Biosci. 14, 2386–2399 (2009).

    CAS  PubMed Central  Google Scholar 

  116. Bosco, R. et al. Fine tuning of protein kinase C (PKC) isoforms in cancer: shortening the distance from the laboratory to the bedside. Mini Rev. Med. Chem. 11, 185–199 (2011).

    CAS  PubMed  Google Scholar 

  117. Teicher, B. A. Protein kinase C as a therapeutic target. Clin. Cancer Res. 12, 5336–5345 (2006).

    CAS  PubMed  Google Scholar 

  118. Budas, G. R., Churchill, E. N. & Mochly-Rosen, D. Cardioprotective mechanisms of PKC isozyme-selective activators and inhibitors in the treatment of ischemia-reperfusion injury. Pharmacol. Res. 55, 523–536 (2007).

    CAS  PubMed  Google Scholar 

  119. Pravdic, D. et al. Anesthetic-induced preconditioning delays opening of mitochondrial permeability transition pore via protein Kinase C-ɛ-mediated pathway. Anesthesiology 111, 267–274 (2009).

    CAS  PubMed  Google Scholar 

  120. Philip, P. A. et al. Phase I study of bryostatin 1: assessment of interleukin 6 and tumor necrosis factor α induction in vivo. J. Natl Cancer Inst. 85, 1812–1818 (1993).

    CAS  PubMed  Google Scholar 

  121. Propper, D. J. et al. A phase II study of bryostatin 1 in metastatic malignant melanoma. Br. J. Cancer 78, 1337–1341 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Gonzalez, R., Ebbinghaus, S., Henthorn, T. K., Miller, D. & Kraft, A. S. Treatment of patients with metastatic melanoma with bryostatin-1 — a phase II study. Melanoma Res. 9, 599–606 (1999).

    CAS  PubMed  Google Scholar 

  123. Bedikian, A. Y. et al. Phase II evaluation of bryostatin-1 in metastatic melanoma. Melanoma Res. 11, 183–188 (2001).

    CAS  PubMed  Google Scholar 

  124. Brockstein, B. et al. Phase II studies of bryostatin-1 in patients with advanced sarcoma and advanced head and neck cancer. Invest. New Drugs 19, 249–254 (2001).

    CAS  PubMed  Google Scholar 

  125. Varterasian, M. L. et al. Phase II study of bryostatin 1 in patients with relapsed multiple myeloma. Invest. New Drugs 19, 245–247 (2001).

    CAS  PubMed  Google Scholar 

  126. Zonder, J. A. et al. A phase II trial of bryostatin 1 in the treatment of metastatic colorectal cancer. Clin. Cancer Res. 7, 38–42 (2001).

    CAS  PubMed  Google Scholar 

  127. Pfister, D. G. et al. A phase II trial of bryostatin-1 in patients with metastatic or recurrent squamous cell carcinoma of the head and neck. Invest. New Drugs 20, 123–127 (2002).

    CAS  PubMed  Google Scholar 

  128. Winegarden, J. D. et al. A phase II study of bryostatin-1 and paclitaxel in patients with advanced non-small cell lung cancer. Lung Cancer 39, 191–196 (2003).

    PubMed  Google Scholar 

  129. Nezhat, F. et al. Phase II trial of the combination of bryostatin-1 and cisplatin in advanced or recurrent carcinoma of the cervix: a New York Gynecologic Oncology Group study. Gynecol. Oncol. 93, 144–148 (2004).

    CAS  PubMed  Google Scholar 

  130. Lam, A. P. et al. Phase II study of paclitaxel plus the protein kinase C inhibitor bryostatin-1 in advanced pancreatic carcinoma. Am. J. Clin. Oncol. 33, 121–124 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Haas, N. B. et al. Weekly bryostatin-1 in metastatic renal cell carcinoma: a phase II study. Clin. Cancer Res. 9, 109–114 (2003).

    CAS  PubMed  Google Scholar 

  132. Madhusudan, S. et al. A multicentre phase II trial of bryostatin-1 in patients with advanced renal cancer. Br. J. Cancer 89, 1418–1422 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Ajani, J. A. et al. A multi-center phase II study of sequential paclitaxel and bryostatin-1 (NSC 339555) in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma. Invest. New Drugs 24, 353–357 (2006). This is one of several small studies showing a modest partial response rate with bryostatin 1, but with unacceptable toxicity. The study was discontinued owing to grade 3 or grade 4 myalgias in 50% of patients.

    CAS  PubMed  Google Scholar 

  134. Ku, G. Y. et al. Phase II trial of sequential paclitaxel and 1 h infusion of bryostatin-1 in patients with advanced esophageal cancer. Cancer Chemother. Pharmacol. 62, 875–880 (2008).

    CAS  PubMed  Google Scholar 

  135. Cripps, M. C. et al. Phase II randomized study of ISIS 3521 and ISIS 5132 in patients with locally advanced or metastatic colorectal cancer: a National Cancer Institute of Canada clinical trials group study. Clin. Cancer Res. 8, 2188–2192 (2002).

    CAS  PubMed  Google Scholar 

  136. Tolcher, A. W. et al. A randomized phase II and pharmacokinetic study of the antisense oligonucleotides ISIS 3521 and ISIS 5132 in patients with hormone-refractory prostate cancer. Clin. Cancer Res. 8, 2530–2535 (2002).

    CAS  PubMed  Google Scholar 

  137. Marshall, J. L. et al. A phase II trial of ISIS 3521 in patients with metastatic colorectal cancer. Clin. Colorectal Cancer 4, 268–274 (2004).

    CAS  PubMed  Google Scholar 

  138. Advani, R. et al. A phase I trial of aprinocarsen (ISIS 3521/LY900003), an antisense inhibitor of protein kinase C-α administered as a 24-hour weekly infusion schedule in patients with advanced cancer. Invest. New Drugs 23, 467–477 (2005).

    CAS  PubMed  Google Scholar 

  139. Rao, S. et al. Phase II study of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase Cα, in patients with previously treated low-grade non-Hodgkin's lymphoma. Ann. Oncol. 15, 1413–1418 (2004).

    CAS  PubMed  Google Scholar 

  140. Lynch, T. J. et al. Randomized phase III trial of chemotherapy and antisense oligonucleotide LY9000003 (ISIS 3521) in patients with advanced NSCLC: initial report. Proc. Am. Soc. Clin. Oncol. 22, 623 (2003).

    Google Scholar 

  141. Paz-Ares, L. et al. Phase III study of gemcitabine and cisplatin with or without aprinocarsen, a protein kinase C-α antisense oligonucleotide, in patients with advanced-stage non-small-cell lung cancer. J. Clin. Oncol. 24, 1428–1434 (2006).

    CAS  PubMed  Google Scholar 

  142. Robertson, M. J. et al. Phase II study of enzastaurin, a protein kinase Cβ inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. J. Clin. Oncol. 25, 1741–1746 (2007).

    CAS  PubMed  Google Scholar 

  143. Morschhauser, F. et al. A phase II study of enzastaurin, a protein kinase Cβ inhibitor, in patients with relapsed or refractory mantle cell lymphoma. Ann. Oncol. 19, 247–253 (2008).

    CAS  PubMed  Google Scholar 

  144. Oh, Y. et al. Enzastaurin, an oral serine/threonine kinase inhibitor, as second- or third-line therapy of non-small-cell lung cancer. J. Clin. Oncol. 26, 1135–1141 (2008).

    CAS  PubMed  Google Scholar 

  145. Glimelius, B. et al. A window of opportunity phase II study of enzastaurin in chemonaive patients with asymptomatic metastatic colorectal cancer. Ann. Oncol. 21, 1020–1026 (2010).

    CAS  PubMed  Google Scholar 

  146. Kreisl, T. N. et al. A phase I/II trial of enzastaurin in patients with recurrent high-grade gliomas. Neuro Oncol. 12, 181–189 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Usha, L. et al. A Gynecologic Oncology Group phase II trial of the protein kinase C-β inhibitor, enzastaurin and evaluation of markers with potential predictive and prognostic value in persistent or recurrent epithelial ovarian and primary peritoneal malignancies. Gynecol. Oncol. 121, 455–461 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Socinski, M. A. et al. Randomized, phase II trial of pemetrexed and carboplatin with or without enzastaurin versus docetaxel and carboplatin as first-line treatment of patients with stage IIIB/IV non-small cell lung cancer. J. Thorac. Oncol. 5, 1963–1969 (2010).

    PubMed  Google Scholar 

  149. Couldwell, W. T. et al. Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen. Clin. Cancer Res. 2, 619–622 (1996).

    CAS  PubMed  Google Scholar 

  150. Bergan, R. C. et al. A Phase II study of high-dose tamoxifen in patients with hormone-refractory prostate cancer. Clin. Cancer Res. 5, 2366–2373 (1999).

    CAS  PubMed  Google Scholar 

  151. Robins, H. I. et al. Phase 2 trial of radiation plus high-dose tamoxifen for glioblastoma multiforme: RTOG protocol BR-0021. Neuro Oncol. 8, 47–52 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Millward, M. J. et al. The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study. Br. J. Cancer 95, 829–834 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Fischer, T. et al. Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J. Clin. Oncol. 28, 4339–4345 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Rini, B. I. et al. Time to disease progression to evaluate a novel protein kinase C inhibitor, UCN-01, in renal cell carcinoma. Cancer 101, 90–95 (2004).

    CAS  PubMed  Google Scholar 

  155. Welch, S. et al. UCN-01 in combination with topotecan in patients with advanced recurrent ovarian cancer: a study of the Princess Margaret Hospital Phase II consortium. Gynecol. Oncol. 106, 305–310 (2007).

    CAS  PubMed  Google Scholar 

  156. Packer, M. et al. Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure. Principal Investigators of the REFLECT Study. J. Am. Coll. Cardiol. 22, 65–72 (1993).

    CAS  PubMed  Google Scholar 

  157. DeMets, D. L. & Califf, R. M. Lessons learned from recent cardiovascular clinical trials: part II. Circulation 106, 880–886 (2002).

    PubMed  Google Scholar 

  158. Aiello, L. P. et al. Oral protein kinase Cβ inhibition using ruboxistaurin: efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with diabetic retinopathy in the protein kinase Cβ inhibitor-diabetic retinopathy study and the protein kinase Cβ inhibitor-diabetic retinopathy study 2. Retina 31, 2084–2094 (2011).

    CAS  PubMed  Google Scholar 

  159. Ladage, D. et al. Inhibition of PKC α/β with ruboxistaurin antagonizes heart failure in pigs after myocardial infarction injury. Circ. Res. 109, 1396–1400 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Churchill, E. N. & Mochly-Rosen, D. The roles of PKCδ and ɛ isoenzymes in the regulation of myocardial ischaemia/reperfusion injury. Biochem. Soc. Trans. 35, 1040–1042 (2007).

    CAS  PubMed  Google Scholar 

  161. Julier, K. et al. Preconditioning by sevoflurane decreases biochemical markers for myocardial and renal dysfunction in coronary artery bypass graft surgery: a double-blinded, placebo-controlled, multicenter study. Anesthesiology 98, 1315–1327 (2003).

    CAS  PubMed  Google Scholar 

  162. Guarracino, F. et al. Myocardial damage prevented by volatile anesthetics: a multicenter randomized controlled study. J. Cardiothorac. Vasc. Anesth. 20, 477–483 (2006).

    CAS  PubMed  Google Scholar 

  163. Lee, M. C. et al. Isoflurane preconditioning-induced cardio-protection in patients undergoing coronary artery bypass grafting. Eur. J. Anaesthesiol. 23, 841–847 (2006).

    CAS  PubMed  Google Scholar 

  164. Tritapepe, L. et al. Cardiac protection by volatile anaesthetics: a multicentre randomized controlled study in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Eur. J. Anaesthesiol. 24, 323–331 (2007).

    CAS  PubMed  Google Scholar 

  165. De Hert, S. et al. A comparison of volatile and non volatile agents for cardioprotection during on-pump coronary surgery. Anaesthesia 64, 953–960 (2009). In this randomized study of 414 patients undergoing CABG, those receiving volatile anaesthetics had reduced 1-year mortality compared to those receiving total intravenous anaesthesia.

    CAS  PubMed  Google Scholar 

  166. Mentzer, R. M. Jr. et al. Adenosine myocardial protection: preliminary results of a phase II clinical trial. Ann. Surg. 229, 643–649; discussion 649–650 (1999).

    PubMed  PubMed Central  Google Scholar 

  167. Belhomme, D. et al. Is adenosine preconditioning truly cardioprotective in coronary artery bypass surgery? Ann. Thorac. Surg. 70, 590–594 (2000).

    CAS  PubMed  Google Scholar 

  168. Jin, Z. et al. The myocardial protective effects of adenosine pretreatment in children undergoing cardiac surgery: a randomized controlled clinical trial. Eur. J. Cardiothorac. Surg. 39, e90–e96 (2011).

    PubMed  Google Scholar 

  169. Mangano, D. T., Miao, Y., Tudor, I. C. & Dietzel, C. Post-reperfusion myocardial infarction: long-term survival improvement using adenosine regulation with acadesine. J. Am. Coll. Cardiol. 48, 206–214 (2006).

    PubMed  Google Scholar 

  170. Newman, M. F. et al. Effect of adenosine-regulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: the RED-CABG randomized controlled trial. JAMA 308, 157–164 (2012). This large, randomized study comparing the effect of acadesine versus placebo on the composite end point of mortality, nonfatal stroke and severe left ventricular dysfunction in patients undergoing CABG was stopped prematurely for futility.

    CAS  PubMed  Google Scholar 

  171. Ross, A. M., Gibbons, R. J., Stone, G. W., Kloner, R. A. & Alexander, R. W. A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II). J. Am. Coll. Cardiol. 45, 1775–1780 (2005). In this randomized trial of 2,118 patients, adenosine failed to reduce the 6-month incidence of heart failure or death compared to placebo.

    CAS  PubMed  Google Scholar 

  172. Bates, E. et al. Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction. Circulation 117, 886–896 (2008).

    PubMed  Google Scholar 

  173. Lincoff, A. M. Selective inhibition of delta protein kinase C to reduce infarct size after primary percutaneous intervention for acute myocardial infarction: the PROTECTION-AMI Phase 2b clinical trial. theheart.org website[online], (2011).

  174. PKC–DRS Study Group. The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the Protein Kinase Cβ Inhibitor Diabetic Retinopathy Study (PKC-DRS) multicenter randomized clinical trial. Diabetes 54, 2188–2197 (2005).

  175. Aiello, L. P. et al. Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy. Ophthalmology 113, 2221–2230 (2006).

    PubMed  Google Scholar 

  176. Sheetz, M. J. et al. Effect of ruboxistaurin (RBX) on visual acuity decline over a 6-year period with cessation and reinstitution of therapy: results of an open-label extension of the Protein Kinase C Diabetic Retinopathy Study 2 (PKC-DRS2). Retina 31, 1053–1059 (2011). In this long-term study, patients with moderate to severe nonproliferative diabetic retinopathy who received ruboxistaurin for 5 years versus 2 years had a much lower incidence of SMVL (8% versus 26%).

    CAS  PubMed  Google Scholar 

  177. PKC–DMES Study Group. Effect of ruboxistaurin in patients with diabetic macular edema: thirty-month results of the randomized PKC-DMES clinical trial. Arch. Ophthalmol. 125, 318–324 (2007).

  178. Campochiaro, P. A. Reduction of diabetic macular edema by oral administration of the kinase inhibitor PKC412. Invest. Ophthalmol. Vis. Sci. 45, 922–931 (2004).

    PubMed  Google Scholar 

  179. Tuttle, K. R. et al. The effect of ruboxistaurin on nephropathy in type 2 diabetes. Diabetes Care 28, 2686–2690 (2005).

    CAS  PubMed  Google Scholar 

  180. Tuttle, K. R., McGill, J. B., Haney, D. J., Lin, T. E. & Anderson, P. W. Kidney outcomes in long-term studies of ruboxistaurin for diabetic eye disease. Clin. J. Am. Soc. Nephrol. 2, 631–636 (2007).

    CAS  PubMed  Google Scholar 

  181. Vinik, A. I. et al. Treatment of symptomatic diabetic peripheral neuropathy with the protein kinase Cβ-inhibitor ruboxistaurin mesylate during a 1-year, randomized, placebo-controlled, double-blind clinical trial. Clin. Ther. 27, 1164–1180 (2005).

    CAS  PubMed  Google Scholar 

  182. Casellini, C. M. et al. A 6-month, randomized, double-masked, placebo-controlled study evaluating the effects of the protein kinase C-β inhibitor ruboxistaurin on skin microvascular blood flow and other measures of diabetic peripheral neuropathy. Diabetes Care 30, 896–902 (2007).

    CAS  PubMed  Google Scholar 

  183. Bebchuk, J. M. et al. A preliminary investigation of a protein kinase C inhibitor in the treatment of acute mania. Arch. Gen. Psychiatry 57, 95–97 (2000).

    CAS  PubMed  Google Scholar 

  184. Zarate, C. A. Jr. et al. Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study. Bipolar Disord. 9, 561–570 (2007).

    CAS  PubMed  Google Scholar 

  185. Yildiz, A., Guleryuz, S., Ankerst, D. P., Ongur, D. & Renshaw, P. F. Protein kinase C inhibition in the treatment of mania: a double-blind, placebo-controlled trial of tamoxifen. Arch. Gen. Psychiatry 65, 255–263 (2008). This study showed that inpatients with acute mania who received tamoxifen rather than placebo had significant improvement in their Young Mania Rating Scale.

    CAS  PubMed  Google Scholar 

  186. Amrollahi, Z. et al. Double-blind, randomized, placebo-controlled 6-week study on the efficacy and safety of the tamoxifen adjunctive to lithium in acute bipolar mania. J. Affect Disord. 129, 327–331 (2011).

    CAS  PubMed  Google Scholar 

  187. Budde, K. et al. Sotrastaurin, a novel small molecule inhibiting protein kinase C: first clinical results in renal-transplant recipients. Am. J. Transplant. 10, 571–581 (2010).

    CAS  PubMed  Google Scholar 

  188. Friman, S. et al. Sotrastaurin, a novel small molecule inhibiting protein-kinase C: randomized phase II study in renal transplant recipients. Am. J. Transplant. 11, 1444–1455 (2011). In this study, individuals randomized to an immunosuppressive regimen containing sotrastaurin instead of tacrolimus had a much higher incidence of acute graft rejection.

    CAS  PubMed  Google Scholar 

  189. Begely, C. G. & Ellis, L. M. Raise standards for preclinical cancer reseach. Nature 483, 531–533 (2012). This is a good commentary about the challenge of translating preclinical data to successful clinical trials.

    Google Scholar 

  190. Davis, M. I. et al. Comprehensive analysis of kinase inhibitor selectivity. Nature Biotech. 29, 1046–1051 (2011).

    CAS  Google Scholar 

  191. Saxena, C., Zhen, E., Higgs, R. E. & Hale, J. E. An immuno-chemo-proteomics method for drug target deconvolution. J. Proteome Res. 7, 3490–3497 (2008).

    CAS  PubMed  Google Scholar 

  192. Harper, M. T. & Poole, A. W. Diverse functions of protein kinase C isoforms in platelet activation and thrombus formation. J. Thromb. Haemost. 8, 454–462 (2010).

    CAS  PubMed  Google Scholar 

  193. Duquesnes, N., Lezoualc'h, F. & Crozatier, B. PKC-delta and PKC-epsilon: foes of the same family or strangers? J. Mol. Cell. Cardiol. 51, 665–673 (2011).

    CAS  PubMed  Google Scholar 

  194. Yang, X., Cohen, M. V. & Downey, J. M. Mechanism of cardioprotection by early ischemic preconditioning. Cardiovasc. Drugs Ther. 24, 225–234 (2010).

    PubMed  PubMed Central  Google Scholar 

  195. Chen, C. H. et al. Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science 321, 1493–1495 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Ikeno, F., Inagaki, K., Rezaee, M. & Mochly-Rosen, D. Impaired perfusion after myocardial infarction is due to reperfusion-induced δPKC-mediated myocardial damage. Cardiovasc. Res. 73, 699–709 (2007).

    CAS  PubMed  Google Scholar 

  197. Ferreira, J. C., Mochly-Rosen, D. & Boutjdir, M. Regulation of cardiac excitability by protein kinase C isozymes. Front. Biosci. 4, 532–546 (2012).

    Google Scholar 

  198. Inagaki, K., Koyanagi, T., Berry, N. C., Sun, L. & Mochly-Rosen, D. Pharmacological inhibition of ɛ-protein kinase C attenuates cardiac fibrosis and dysfunction in hypertension-induced heart failure. Hypertension 51, 1565–1569 (2008).

    CAS  PubMed  Google Scholar 

  199. Braz, J. C. et al. PKC-α regulates cardiac contractility and propensity toward heart failure. Nature Med. 10, 248–254 (2004).

    CAS  PubMed  Google Scholar 

  200. Braun, M. U. & Mochly-Rosen, D. Opposing effects of δ- and ζ-protein kinase C isozymes on cardiac fibroblast proliferation: use of isozyme-selective inhibitors. J. Mol. Cell. Cardiol. 35, 895–903 (2003).

    CAS  PubMed  Google Scholar 

  201. Liu, Q. & Molkentin, J. D. Protein kinase Cα as a heart failure therapeutic target. J. Mol. Cell. Cardiol. 51, 474–478 (2011).

    CAS  PubMed  Google Scholar 

  202. Hoyt, R. E. & Bowling, L. S. Reducing readmissions for congestive heart failure. Am. Fam. Physician 63, 1593–1598 (2001).

    CAS  PubMed  Google Scholar 

  203. Simonis, G. et al. Protein kinase C in the human heart: differential regulation of the isoforms in aortic stenosis or dilated cardiomyopathy. Mol. Cell. Biochem. 305, 103–111 (2007).

    CAS  PubMed  Google Scholar 

  204. Bowman, J. C. et al. Expression of protein kinase Cβ in the heart causes hypertrophy in adult mice and sudden death in neonates. J. Clin. Invest. 100, 2189–2195 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Hambleton, M. et al. Pharmacological- and gene therapy-based inhibition of protein kinase Cα/β enhances cardiac contractility and attenuates heart failure. Circulation 114, 574–582 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Huang, L. et al. Increased contractility and altered Ca2+ transients of mouse heart myocytes conditionally expressing PKCβ. Am. J. Physiol. Cell Physiol. 280, C1114–C1120 (2001).

    CAS  PubMed  Google Scholar 

  207. Roman, B. B., Geenen, D. L., Leitges, M. & Buttrick, P. M. PKC-β is not necessary for cardiac hypertrophy. Am. J. Physiol. Heart Circ. Physiol. 280, H2264–H2270 (2001).

    CAS  PubMed  Google Scholar 

  208. Takeishi, Y. et al. In vivo phosphorylation of cardiac troponin I by protein kinase Cβ2 decreases cardiomyocyte calcium responsiveness and contractility in transgenic mouse hearts. J. Clin. Invest. 102, 72–78 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Ferreira, J. C., Boer, B. N., Grinberg, M., Brum, P. C. & Mochly-Rosen, D. Protein quality control disruption by PKCβII in heart failure; rescue by the selective PKCβII inhibitor, βIIV5-3. PLoS ONE 7, e33175 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Connelly, K. A. et al. Inhibition of protein kinase C-β by ruboxistaurin preserves cardiac function and reduces extracellular matrix production in diabetic cardiomyopathy. Circ. Heart Fail. 2, 129–137 (2009).

    CAS  PubMed  Google Scholar 

  211. Ding, R. Q., Tsao, J., Chai, H., Mochly-Rosen, D. & Zhou, W. Therapeutic potential for protein kinase C inhibitor in vascular restenosis. J. Cardiovasc. Pharmacol. Ther. 16, 160–167 (2011).

    CAS  PubMed  Google Scholar 

  212. Deuse, T. et al. Sustained inhibition of epsilon protein kinase C inhibits vascular restenosis after balloon injury and stenting. Circulation 122, S170–S178 (2010).

    CAS  PubMed  Google Scholar 

  213. Griner, E. M. & Kazanietz, M. G. Protein kinase C and other diacylglycerol effectors in cancer. Nature Rev. Cancer 7, 281–294 (2007).

    CAS  Google Scholar 

  214. Blumberg, P. M., Delclos, K. B., Dunphy, W. G. & Jaken, S. Specific binding of phorbol ester tumor promoters to mouse tissues and cultured cells. Carcinog. Compr. Surv. 7, 519–535 (1982).

    CAS  PubMed  Google Scholar 

  215. Kheifets, V., Bright, R., Inagaki, K., Schechtman, D. & Mochly-Rosen, D. Protein kinase Cδ (δPKC)-annexin V interaction: a required step in δPKC translocation and function. J. Biol. Chem. 281, 23218–23226 (2006).

    CAS  PubMed  Google Scholar 

  216. Toker, A. et al. Multiple isoforms of a protein kinase C inhibitor (KCIP-1/14-3-3) from sheep brain — amino acid sequence of phosphorylated forms. Eur. J. Biochem. 206, 453–461 (1992).

    CAS  PubMed  Google Scholar 

  217. Gold, M. G. et al. Architecture and dynamics of an A-kinase anchoring protein 79 (AKAP79) signaling complex. Proc. Natl Acad. Sci. USA 108, 6426–6431 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Klauck, T. M. et al. Coordination of three signaling enzymes by AKAP79, a mammalian scaffold protein. Science 271, 1589–1592 (1996).

    CAS  PubMed  Google Scholar 

  219. Chapline, C. et al. A major, transformation-sensitive PKC-binding protein is also a PKC substrate involved in cytoskeletal remodeling. J. Biol. Chem. 273, 19482–19489 (1998).

    CAS  PubMed  Google Scholar 

  220. Mochly-Rosen, D., Khaner, H., Lopez, J. & Smith, B. L. Intracellular receptors for activated protein kinase C. Identification of a binding site for the enzyme. J. Biol. Chem. 266, 14866–14868 (1991). This paper describes the first rationally designed peptide inhibitor of PKC localization.

    CAS  PubMed  Google Scholar 

  221. Ron, D., Luo, J. & Mochly-Rosen, D. C2 region-derived peptides inhibit translocation and function of β protein kinase C in vivo. J. Biol. Chem. 270, 24180–24187 (1995).

    CAS  PubMed  Google Scholar 

  222. House, C. & Kemp, B. E. Protein kinase C contains a pseudosubstrate prototope in its regulatory domain. Science 238, 1726–1728 (1987). This is the first description of a peptide inhibitor of PKC that acts as a competitive inhibitor of the substrate phosphorylation site.

    CAS  PubMed  Google Scholar 

  223. Ron, D. & Mochly-Rosen, D. An autoregulatory region in protein kinase C: the pseudoanchoring site. Proc. Natl Acad. Sci. USA 92, 492–496 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Dorn, G. W. et al. Sustained in vivo cardiac protection by a rationally designed peptide that causes ɛ protein kinase C translocation. Proc. Natl Acad. Sci. USA 96, 12798–12803 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Inagaki, K. et al. Inhibition of δ-protein kinase C protects against reperfusion injury of the ischemic heart in vivo. Circulation 108, 2304–2307 (2003).

    CAS  PubMed  Google Scholar 

  226. Armstrong, J. S. & Whiteman, M. Measurement of reactive oxygen species in cells and mitochondria. Methods Cell Biol. 80, 355–377 (2007).

    CAS  PubMed  Google Scholar 

  227. Murriel, C. L., Churchill, E., Inagaki, K., Szweda, L. I. & Mochly-Rosen, D. Protein kinase Cδ activation induces apoptosis in response to cardiac ischemia and reperfusion damage: a mechanism involving BAD and the mitochondria. J. Biol. Chem. 279, 47985–47991 (2004).

    CAS  PubMed  Google Scholar 

  228. Konopatskaya, O. & Poole, A. W. Protein kinase Cα: disease regulator and therapeutic target. Trends Pharmacol. Sci. 31, 8–14 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Gorin, M. A. & Pan, Q. Protein kinase Cɛ: an oncogene and emerging tumor biomarker. Mol. Cancer 8, 9 (2009).

    PubMed  PubMed Central  Google Scholar 

  230. Lee, S. K. et al. Apurinic/apyrimidinic endonuclease 1 inhibits protein kinase C-mediated p66shc phosphorylation and vasoconstriction. Cardiovasc. Res. 91, 502–509 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Standaert, M. L. et al. Effects of knockout of the protein kinase Cβ gene on glucose transport and glucose homeostasis. Endocrinology 140, 4470–4477 (1999).

    CAS  PubMed  Google Scholar 

  232. Chen, C. & Mochly-Rosen, D. Opposing effects of δ and ɛPKC in ethanol-induced cardioprotection. J. Mol. Cell. Cardiol. 33, 581–585 (2001).

    CAS  PubMed  Google Scholar 

  233. Mochly-Rosen, D. et al. Cardiotrophic effects of protein kinase Cɛ: analysis by in vivo modulation of PKCɛ translocation. Circ. Res. 86, 1173–1179 (2000).

    CAS  PubMed  Google Scholar 

  234. Koide, Y. et al. Differential induction of protein kinase C isoforms at the cardiac hypertrophy stage and congestive heart failure stage in Dahl salt-sensitive rats. Hypertens. Res. 26, 421–426 (2003).

    CAS  PubMed  Google Scholar 

  235. Limnander, A. et al. STIM1, PKC-δ and RasGRP set a threshold for proapoptotic Erk signaling during B cell development. Nature Immunol. 12, 425–433 (2011).

    CAS  Google Scholar 

  236. Kilpatrick, L. E. et al. Protection against sepsis-induced lung injury by selective inhibition of protein kinase C-δ (δ-PKC). J. Leukoc. Biol. 89, 3–10 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Boschelli, D. H. Small molecule inhibitors of PKCθ as potential antiinflammatory therapeutics. Curr. Top. Med. Chem. 9, 640–654 (2009).

    CAS  PubMed  Google Scholar 

  238. Bright, R., Steinberg, G. K. & Mochly-Rosen, D. δPKC mediates microcerebrovascular dysfunction in acute ischemia and in chronic hypertensive stress in vivo. Brain Res. 1144, 146–155 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. Chou, W. H. & Messing, R. O. Hypertensive encephalopathy and the blood–brain barrier: is δPKC a gatekeeper? J. Clin. Invest. 118, 17–20 (2008).

    CAS  PubMed  Google Scholar 

  240. Qi, X., Disatnik, M. H., Shen, N., Sobel, R. A. & Mochly-Rosen, D. Aberrant mitochondrial fission in neurons induced by protein kinase Cδ under oxidative stress conditions in vivo. Mol. Biol. Cell 22, 256–265 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. Bright, R., Sun, G. H., Yenari, M. A., Steinberg, G. K. & Mochly-Rosen, D. ɛPKC confers acute tolerance to cerebral ischemic reperfusion injury. Neurosci. Lett. 441, 120–124 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  242. Langlois, A. et al. Crucial implication of protein kinase C (PKC)-δ, PKC-ζ, ERK-1/2, and p38 MAPK in migration of human asthmatic eosinophils. J. Leukoc. Biol. 85, 656–663 (2009).

    CAS  PubMed  Google Scholar 

  243. Kanthasamy, A. G. et al. A novel peptide inhibitor targeted to caspase-3 cleavage site of a proapoptotic kinase protein kinase Cδ (PKCδ) protects against dopaminergic neuronal degeneration in Parkinson's disease models. Free Radic. Biol. Med. 41, 1578–1589 (2006).

    CAS  PubMed  Google Scholar 

  244. Sawada, M., Imamura, K. & Nagatsu, T. Role of cytokines in inflammatory process in Parkinson's disease. J. Neural Transm. Suppl. 2006, 373–381 (2006).

    Google Scholar 

  245. Defauw, J. M. et al. Synthesis and protein kinase C inhibitory activities of acyclic balanol analogs that are highly selective for protein kinase C over protein kinase A. J. Med. Chem. 39, 5215–5227 (1996).

    CAS  PubMed  Google Scholar 

  246. Swannie, H. C. & Kaye, S. B. Protein kinase C inhibitors. Curr. Oncol. Rep. 4, 37–46 (2002).

    PubMed  Google Scholar 

  247. Lee, K.-W. et al. Enzastaurin, a protein kinase Cβ inhibitor, suppresses signaling through the ribosomal S6 kinase and bad pathways and induces apoptosis in human gastric cancer. Cancer Res. 68, 1916–1926 (2008).

    CAS  PubMed  Google Scholar 

  248. Gray, M. O., Karliner, J. S. & Mochly-Rosen, D. A selective ɛ-protein kinase C antagonist inhibits protection of cardiac myocytes from hypoxia-induced cell death. J. Biol. Chem. 272, 30945–30951 (1997).

    CAS  PubMed  Google Scholar 

  249. Lahn, M., Sundell, K. & Moore, S. Targeting protein kinase C-α (PKC-α) in cancer with the phosphorothioate antisense oligonucleotide aprinocarsen. Ann. NY Acad. Sci. 1002, 263–270 (2003).

    CAS  PubMed  Google Scholar 

  250. Goekjian, P. G. & Jirousek, M. R. Protein kinase C inhibitors as novel anticancer drugs. Expert Opin. Investig. Drugs 10, 2117–2140 (2001).

    CAS  PubMed  Google Scholar 

  251. Tamaoki, T. Use and specificity of staurosporine, UCN-01, and calphostin C as protein kinase inhibitors. Methods Enzymol. 201, 340–347 (1991).

    CAS  PubMed  Google Scholar 

  252. Kraft, A. S., Smith, J. B. & Berkow, R. L. Bryostatin, an activator of the calcium phospholipid-dependent protein kinase, blocks phorbol ester-induced differentiation of human promyelocytic leukemia cells HL-60. Proc. Natl Acad. Sci. USA 83, 1334–1338 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. Schwarze, S. R., Ho, A., Vocero-Akbani, A. & Dowdy, S. F. In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285, 1569–1572 (1999).

    CAS  PubMed  Google Scholar 

  254. Qi, X., Inagaki, K., Sobel, R. A. & Mochly-Rosen, D. Sustained pharmacological inhibition of δPKC protects against hypertensive encephalopathy through prevention of blood–brain barrier breakdown in rats. J. Clin. Invest. 118, 173–182 (2008).

    CAS  PubMed  Google Scholar 

  255. Kim, J., Thorne, S. H., Sun, L., Huang, B. & Mochly-Rosen, D. Sustained inhibition of PKCα reduces intravasation and lung seeding during mammary tumor metastasis in an in vivo mouse model. Oncogene 30, 323–333 (2011).

    CAS  PubMed  Google Scholar 

  256. Inagaki, K., Begley, R., Ikeno, F. & Mochly-Rosen, D. Cardioprotection by ɛ-protein kinase C activation from ischemia: continuous delivery and antiarrhythmic effect of an ɛ-protein kinase C-activating peptide. Circulation 111, 44–50 (2005).

    CAS  PubMed  Google Scholar 

  257. Drew, B. G. & Kingwell, B. A. Acadesine, an adenosine-regulating agent with the potential for widespread indications. Expert Opin. Pharmacother. 9, 2137–2144 (2008).

    CAS  PubMed  Google Scholar 

  258. Zhao, B. et al. Structural basis for Chk1 inhibition by UCN-01. J. Biol. Chem. 277, 46609–46615 (2002).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank A. Gordon, A. Giachetti and E. Gross for their critical comments on the manuscript. This work was supported by the US National Institutes of Health grant HL52141 (to D.M.-R.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Daria Mochly-Rosen.

Ethics declarations

Competing interests

D.M.-R. is the founder of KAI Pharmaceuticals, and K.V.G. and K.D. are past employees of KAI Pharmaceuticals. However, none of the research in the D.M.-R. laboratory is in collaboration with or supported by the company. Furthermore, the company was recently acquired by Amgen and none of the authors is involved in KAI-related or Amgen-related research.

Related links

Related links

FURTHER INFORMATION

Mochly-Rosen Laboratory

ClinicalTrials.gov website

SPARK Program

Glossary

Isozymes

Enzymes that are members of a related gene family and differ by amino acid composition but catalyse a similar chemical reaction.

Preclinical research

Research carried out on a drug in vitro and in animal models that precedes the testing of the drug in patients.

Diacylglycerol

A component of phospholipid that is generated in the membrane as a result of the activation of specific enzymes (phospholipases), and activates members of the protein kinase C family.

Second messengers

Small molecules that are generated inside cells after a cell surface receptor is activated by its corresponding hormone. This primary signal (hormone binding) is then 'passed' to intracellular enzymes through elevated levels of the intracellular second messenger.

Translocation

A change in the intracellular location of an enzyme resulting from a stimulus. In the case of protein kinase C, activation by diacylglycerol, for example, causes translocation of the activated enzyme from the cytosol to various subcellular organelles and to the plasma membrane.

Cardiac ischaemia

Insufficient blood supply resulting in inadequate delivery of oxygen and nutrients: known as a 'heart attack'.

Vasculogenesis

Also known as angiogenesis; an increase in the number and arboration of blood vessels.

Hyperglycaemia

High blood glucose levels.

β-islet cell

A type of pancreatic cell that produces and secretes insulin.

RACK

Receptor of activated C-kinase; a collective name for isozyme-selective protein kinase C (PKC)-anchoring or -binding proteins. RACKs are usually not PKC substrates but they bind to activated isozymes in a specific and saturable manner.

Mitochondria

Intracellular organelles involved in ATP generation that have a crucial role in inducing cell death in response to a variety of stimuli.

Primary end point

An outcome of a treatment in a clinical trial that is designed to determine whether the treatment is efficacious for drug approval — for example, by the US Food and Drug Administration.

Secondary end point

An outcome of a treatment in a clinical trial that is designed to determine other benefits of the drug treatment in addition to whether the treatment is efficacious for drug approval (the primary end point).

Area under the curve

(AUC). Integration of the amounts of a drug or an enzyme in the blood, sampled at frequent time intervals.

CK-MB

An isoform of creatine kinase that is specific to heart muscle; its release into the bloodstream indicates cardiac damage.

Double-blinded trial

A trial in which both the health-care provider and the patient are not informed on which groups receive the drug or placebo.

Hypertension

High blood pressure; blood pressure in the arteries is increased and the heart must work harder than usual in order to circulate blood.

Separation-of-function inhibitors

SoF inhibitors; molecules designed to distinguish enzyme activity by selectively inhibiting one activity among others. Specific to protein kinase C, SoF inhibitors distinguish isozyme activity by inhibiting phosphorylation of one substrate among several, thus identifying the role of an individual phosphorylation event by a given isozyme.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mochly-Rosen, D., Das, K. & Grimes, K. Protein kinase C, an elusive therapeutic target?. Nat Rev Drug Discov 11, 937–957 (2012). https://doi.org/10.1038/nrd3871

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd3871

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer