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Targeting Cancer with Small-Molecular-Weight Kinase Inhibitors

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Book cover Kinase Inhibitors

Part of the book series: Methods in Molecular Biology ((MIMB,volume 795))

Abstract

Protein and lipid kinases fulfill essential roles in many signaling pathways that regulate normal cell functions. Deregulation of these kinase activities lead to a variety of pathologies ranging from cancer to inflammatory diseases, diabetes, infectious diseases, cardiovascular disorders, cell growth and survival. 518 protein kinases and about 20 lipid-modifying kinases are encoded by the human genome, and a much larger proportion of additional kinases are present in parasite, bacterial, fungal, and viral genomes that are susceptible to exploitation as drug targets. Since many human diseases result from overactivation of protein and lipid kinases due to mutations and/or overexpression, this enzyme class represents an important target for the pharmaceutical industry. Approximately one third of all protein targets under investigation in the pharmaceutical industry are protein or lipid kinases.

The kinase inhibitors that have been launched, thus far, are mainly in oncology indications and are directed against a handful of protein and lipid kinases. With one exception, all of these registered kinase inhibitors are directed toward the ATP-site and display different selectivities, potencies, and pharmacokinetic properties. At present, about 150 kinase-targeted drugs are in clinical development and many more in various stages of preclinical development. Kinase inhibitor drugs that are in clinical trials target all stages of signal transduction from the receptor protein tyrosine kinases that initiate intracellular signaling, through second-messenger-dependent lipid and protein kinases, and protein kinases that regulate the cell cycle.

This review provides an insight into protein and lipid kinase drug discovery with respect to achievements, binding modes of inhibitors, and novel avenues for the generation of second-generation kinase inhibitors to treat cancers.

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Abbreviations

AML:

Acute myeloid leukemia

B-ALL:

B-cell acute lymphoblastic leukemia

CEL:

Chronic eosinophilic leukemia

CML:

Chronic myeloid leukemia

CMML:

Chronic myelomonocytic leukemia

RCC:

Renal cell cancer

NSCLC:

Non-small-cell lung cancer

GIST:

Gastrointestinal stromal cancer

CSF1R:

colony-stimulating factor 1 receptor

EGFR:

Epidermal growth factor receptor

FLT3:

FMS-related tyrosine kinase 3

GIST:

Gastrointestinal stromal tumor

NSCLC:

Non-small-cell lung cancer

PDGFR:

Platelet-derived growth factor receptor

RCC:

Renal cell carcinoma

Ph+:

Philadelphia chromosome positive

VEGFR:

Vascular endothelial growth factor receptor

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Authors and Affiliations

  1. Novartis Institutes for Biomedical Research, Expertise Platform Kinases, Basel, Switzerland

    Doriano Fabbro & Georg Martiny-Baron

  2. Novartis Institutes for Biomedical Research, Structural Biology Platform, Basel, Switzerland

    Sandra W. Cowan-Jacob

  3. Novartis Institutes for Biomedical Research, Global Discovery Chermistry, Basel, Switzerland

    Henrik Möbitz

Authors
  1. Doriano Fabbro
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  2. Sandra W. Cowan-Jacob
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  3. Henrik Möbitz
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  4. Georg Martiny-Baron
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Corresponding author

Correspondence to Doriano Fabbro .

Editor information

Editors and Affiliations

  1. LS für Proteomik und Bioanalytik, Technische Universität München, Emil Erlenmeyer Forum 5, Freising, 85354, Germany

    Bernhard Kuster

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Fabbro, D., Cowan-Jacob, S.W., Möbitz, H., Martiny-Baron, G. (2012). Targeting Cancer with Small-Molecular-Weight Kinase Inhibitors. In: Kuster, B. (eds) Kinase Inhibitors. Methods in Molecular Biology, vol 795. Humana Press. https://doi.org/10.1007/978-1-61779-337-0_1

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  • DOI: https://doi.org/10.1007/978-1-61779-337-0_1

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