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Cancer pp 83-132 | Cite as

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

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

Abstract

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 

Abbreviations

Abl

Abelson leukemia virus tyrosine kinase

Akt

Protein kinase B (PKB)

AUC

Area under the curve

Bcr-Abl

Breakpoint cluster region–Abelson leukemia virus tyrosine kinase

bid

Twice a day

CDK2

Cyclin-dependent kinase 2

CML

Chronic myelogenous leukemia

DLT

Dose-limiting toxicity

EGF

Epidermal growth factor

EGFR (ErbB1, HER-1)

Epidermal growth factor receptor

ErbB2

HER-2

ErbB3

HER-3

ErbB4

HER-4

ERK1/2

Extracellular signal-regulated kinase 1/2

ERK5

Extracellular-signal regulated kinase 5

FAK

Focal adhesion kinase

FGF

Fibroblast growth factor

FGFR

Fibroblast growth factor receptor

FISH

Fluorescence in situ hybridization

Flt1

Fms-like tyrosine kinase 1

Flt3

Fms-like tyrosine kinase 3

HER

Human epidermal growth factor receptor

HGFR

Hepatocyte growth factor receptor

Hsp27

Heat shock protein 27

Hsp90

Heat shock protein 90

IGF-1R

Insulin-like growth factor-1 receptor

IR

Insulin receptor

IRK

Insulin receptor kinase

JAK

Janus kinase

KDR (VEGFR2)

Kinase domain receptor (vascular endothelial growth factor receptor 2)

MEK1/2

Mitogen-activated protein kinase kinase 1/2

MTD

Maximum tolerated dose

NSCLC

Non-small cell lung cancer

P38

p38 Mitogen-activated protein kinase

PAK

p21 Activated kinase

PBMC

Peripheral blood mononuclear cells

PDGFR

Platelet-derived growth factor receptor

PFS

Progression-free survival

PI-3 kinase

Phosphatidylinositol 3-kinase

PKA

Protein kinase A or cAMP-dependent protein kinase

PMA

Phorbol 12-myristate 13-acetate

qd

Once a day

RCC

Renal cell carcinoma

RMSD

Root mean square deviation

SCID

Severe combined immunodeficiency

SOS

Son of sevenless

STAT

Signal transducer and activator of transcription

TGFα

Transforming growth factor α

TGI

Tumor growth inhibition

tid

three times a day

VEGF

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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