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

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Cancer

Part of the book series: Topics in Medicinal Chemistry ((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.

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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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  1. Array BioPharma, Inc., 3200 Walnut Street, 80301, Boulder, CO, USA

    Eli M. Wallace, Tammie C. Yeh, Ellen R. Laird, James F. Blake & Joseph Lyssikatos

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  2. Tammie C. Yeh
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Wallace, E.M., Yeh, T.C., Laird, E.R., Blake, J.F., Lyssikatos, J. (2006). Inhibition of Growth Factor Signaling by Small-Molecule Inhibitors of ErbB, Raf, and MEK. In: Bradbury, R.H. (eds) Cancer. Topics in Medicinal Chemistry, vol 1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7355_2006_004

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