Inhibitor SourceBook™ Second Edition

Raf Kinase Inhibitors
Raf kinases are a group of serine/threonine kinases
that include A-Raf, B-Raf, and c-Raf1. A-Raf is
abundant in urogenital tissues, B-Raf is predominantly
expressed in neural tissue, and c-Raf1 is ubiquitous
in its distribution. Raf kinases play an important
role as extracellular signal-regulating kinases in cell
differentiation, proliferation, and apoptosis. The three
Raf proteins share a common structure consisting of an
N-terminal regulatory domain and a C-terminal kinase
domain. Each Raf has three conserved regions, CR1,
CR2, and CR3. In the regulatory domain, CR1 contains
a Ras-binding domain and a cysteine-rich domain, CR2
is a serine/threonine-rich domain, and CR3 contains
the kinase domain and is essential for Raf activity.
The removal of the regulatory domain generates an
oncogenic kinase.
All three Raf proteins also share common mechanisms
of activation and downstream effectors. They work at
the entry point of the mitogen-activated protein kinase/
extracellular-signal-regulated kinase (MAPK/ERK)
pathway, a signaling module that connects cell-surface
receptors and Ras proteins to nuclear transcription
factors. They serve as downstream effectors of Ras
signaling; however, the interaction between Ras and Raf
alone is not sufficient for full activation of Raf kinases.
Raf Kinase Inhibitors
Calbiochem • Inhibitor SourceBook
Phosphorylation/Dephosphorylation
Additional proteins and enzymes are required for full
activation. 14-3-3 proteins are known to bind directly
to Raf and their binding to Ser 621 of Raf-1 is essential
to keep Raf in an inactive, but activation-competent
confirmation. PKA is reported to phosphorylate Ser 43
and Ser 621 and prevent the activation of Raf1. Inhibition
of PKA has been linked to the growth factor-induced
activation of c-Raf1. Ser 728 in the 14-3-3 binding
region in B-Raf is also known to be a target for PKA
phosphorylation.
Abnormal activation of Raf signaling pathway is
common in several type of cancers. Hence, there is
a significant interest in the development of specific
inhibitors that may reverse the progression of these
tumors. These inhibitors may block the expression of Raf
protein, block its interaction with Ras, or block its kinase
activity.
References:
OíNeill, E., and Kolch, W. 2004. Br. J. Cancer. 90, 283.
Bollag, G., et al. 2003. Curr. Opin. Investig. Drugs 4, 436.
Chong, H., et al. 2003. Cell Signal. 15, 463.
Kolch, W., et al. 2002. Expert Rev. Mol. Med. 25, .
Product Cat. No. Comments Size Price
Raf Kinase Inhibitor I 553008 {5-Iodo-3-[(3,5-dibromo-4-hydroxyphenyl)methylene]-2-indolinone}
A potent c-Raf kinase inhibitor (IC 50 = 9 nM). Shows ≥ 00-fold selectivity for
Raf kinase versus Cdk , Cdk2, c-src, ERK2, MEK, p38, Tie2, VEGFR2, and c-fms.
N InSolution Raf
Kinase Inhibitor I
More online... www.calbiochem.com/inhibitors/Raf
mg $99
553003 A 0 mM (500 mg/96 ml) solution of Raf Inhibitor I (Cat. No. 553008) in DMSO. 500 mg $63
ZM 336372 692000 {N-[5-(3-Dimethylaminobenzamido)-2-methylphenyl]-4-hydroxybenzamide}
A potent, specific, and competitive inhibitor of c-Raf (IC 50 = 70 nM). Inhibits c-Raf with
ten-fold greater potency compared to B-Raf. Has no significant effect on many other
protein kinases tested (even at 50 mM) with the exception of SAPK2a/p38a
(IC 50 = 2 mM) and SAPK2b/p38b2 (IC 50 = 2 mM).
mg $ 27
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