Novel anticancer drug discovery

https://doi.org/10.1016/S1367-5931(99)80073-8Get rights and content

There is at present, much optimism about the possibility of finding selective anticancer drugs that will eliminate the cytotoxic side effects associated with conventional cancer chemotherapy. This hope is based on uncovering many novel molecular targets that are ‘cancer-specific’, which will allow the targeting of cancer cells while normal cells are spared. Thus far, encouraging results have been obtained with several of these novel agents at the preclinical level, and clinical trials have begun. These targets are involved at one level or more in tumor biology, including tumor cell proliferation, angiogenesis and metastasis. Novel targets for which advances are being made include the following: growth factor receptor tyrosine kinases such as the epidermal growth factor receptor and HER-2/neu (proliferation); the vascular endothelial growth factor receptor and the basic fibroblast growth factor receptor (angiogenesis); the oncogenic GTP-binding protein Ras (especially agents targeting Ras farnesylation, farnesyltransferase inhibitors) (proliferation); protein kinase C (proliferation and drug resistance); cyclin-dependent kinases (proliferation); and matrix metalloproteinases and angiogenin (angiogenesis and metastasis). Less explored, but potentially useful targets include the receptor tyrosine kinase plateletderived growth factor receptor, mitogen-activated protein kinase cascade oncogenes such as Raf-1 and mitogenactivated protein kinase kinase, cell adhesion molecules such as integrins, anti-apoptosis proteins such as Bcl-2, MDM2 and survivin, and the cell life-span target telomerase.

References and recommended reading (61)

  • OlsonMF et al.

    Signals from Ras and Rho GTPases interact to regulate expression of p21Waf1/Cip1

    Nature

    (1998)
  • Khosravi-FarR et al.

    Increasing complexity of Ras signal transduction: involvement of Rho family proteins

    Adv Cancer Res

    (1998)
  • TzaharE et al.

    The ErbB-2/HER2 oncogenic receptor of adenocarcinomas: from orphanhood to multiple stromal ligands

    Biochim Biophys Acta

    (1998)
  • FarahRA et al.

    The development of monoclonal antibodies for the therapy of cancer

    Crit Rev Eukaryot Gene Exp

    (1998)
  • YeD et al.

    Augmentation of of a humanized anti HER2 mAB 4D5 induced growth inhibition by human-mouse chimeric anti-EGF receptor mAB C225

    Oncogene

    (1998)
  • KlutchkoSR et al.

    2-Substituted aminopyrido[23-d]pyrimidin-7 (8H) -ones. Structure-activity relationships against selected tyrosine kinases and in vitro and in vivo anticancer activity

    J Med Chem

    (1998)
  • Trump-KallmeyerS et al.

    Development of a binding model of protein tyrosine kinase for substituted pyrido[2,3-d]pyrimidine inhibitors

    J Med Chem

    (1998)
  • FongTAT et al.

    SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types

    Cancer Res

    (1999)
  • YaoZ-J et al.

    Potent inhibitors of Grb2 SH2 domain binding by non-phosphate-containing ligands

    J Med Chem

    (1999)
  • Boriack-SjodinPA et al.

    The structural basis of the activation of Ras by Sos

    Nature

    (1998)
  • LeeTR et al.

    Acquisition of high-affinity SH2-targeted ligands via a spatially focused library

    J Med Chem

    (1999)
  • LobellRB et al.

    Pre-clinical development of farnesyltransferase inhibitors

    Cancer Metastasis Rev

    (1998)
  • MallamsAK et al.

    Inhibitors of farnesyl protein transferase. 4-amido, 4-carbamoyl, and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl) piperazine and 1-(3-Bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl) piperazine

    J Med Chem

    (1998)
  • NjorongeFG et al.

    Potent, selective, and orally bioavailable tricyclic pyridyl acetamide N-oxide inhibitors of farnesyl protein transferase with enhanced in vivo antitumor activity

    J Med Chem

    (1998)
  • LongSB et al.

    Cocrystal structure of protein farnesyltransferase complexed with a farnesyl diphosphate substrate

    Biochemistry

    (1998)
  • LebowitzPF et al.

    Non-Ras targets of farnesyltransferase inhibitors: focus on Rho

    Oncogene

    (1998)
  • BernhardEJ et al.

    Inhibiting Ras prenylation increases the radiosensitivity of human tumor cell lines with activating Ras oncogenes

    Cancer Res

    (1998)
  • HunterT

    Oncoprotein networks

    Cell

    (1997)
  • MoniaBP

    First-and second-generation antisense inhibitors targeted to human c-raf kinase: in vitro and in vivo studies

    Anticancer Drug Des

    (1997)
  • CapronigroF et al.

    Protein kinase C: a worthwhile target for anticancer drugs?

    Anticancer Drugs

    (1997)
  • Cited by (0)

    View full text