Cancer pp 83-132 | Cite as

Inhibition of Growth Factor Signaling by Small-Molecule Inhibitors of ErbB, Raf, and MEK

Part of the Topics in Medicinal Chemistry book series (TMC, volume 1)


Approval of Gleevec and its demonstrated therapeutic value marked the full recognition of kinase inhibitorsas a relevant means of cancer treatment. A significant number of kinase inhibitors have recentlyentered clinical practice for the treatment of a variety of cancers and many others are in advancedstages of clinical research. Among these are several promising agents that act in the pathway that initiateswith the growth factor receptors EGFR/ErbB2 and signals through Raf and MEK to the MAP kinase ERK. Thischapter focuses on the biological rationale, enzymatic and pharmacological properties, and clinical statusof several inhibitors of EGFR/ErbB2, Raf, and MEK1/2. Coverage is given of those compounds that have gainedapproval or are being evaluated in human clinical trials.

EGFR inhibitor ErbB2 inhibitor Raf inhibitor MEK inhibitor Kinase inhibitor Cancer ERK 



Abelson leukemia virus tyrosine kinase


Protein kinase B (PKB)


Area under the curve


Breakpoint cluster region–Abelson leukemia virus tyrosine kinase


Twice a day


Cyclin-dependent kinase 2


Chronic myelogenous leukemia


Dose-limiting toxicity


Epidermal growth factor

EGFR (ErbB1, HER-1)

Epidermal growth factor receptor








Extracellular signal-regulated kinase 1/2


Extracellular-signal regulated kinase 5


Focal adhesion kinase


Fibroblast growth factor


Fibroblast growth factor receptor


Fluorescence in situ hybridization


Fms-like tyrosine kinase 1


Fms-like tyrosine kinase 3


Human epidermal growth factor receptor


Hepatocyte growth factor receptor


Heat shock protein 27


Heat shock protein 90


Insulin-like growth factor-1 receptor


Insulin receptor


Insulin receptor kinase


Janus kinase


Kinase domain receptor (vascular endothelial growth factor receptor 2)


Mitogen-activated protein kinase kinase 1/2


Maximum tolerated dose


Non-small cell lung cancer


p38 Mitogen-activated protein kinase


p21 Activated kinase


Peripheral blood mononuclear cells


Platelet-derived growth factor receptor


Progression-free survival

PI-3 kinase

Phosphatidylinositol 3-kinase


Protein kinase A or cAMP-dependent protein kinase


Phorbol 12-myristate 13-acetate


Once a day


Renal cell carcinoma


Root mean square deviation


Severe combined immunodeficiency


Son of sevenless


Signal transducer and activator of transcription


Transforming growth factor α


Tumor growth inhibition


three times a day


Vascular endothelial growth factor


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Copyright information

© Springer-Verlag Berlin Heidelberg 2006

Authors and Affiliations

  1. 1.Array BioPharma, Inc.BoulderUSA

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