Format

Send to

Choose Destination
J Med Chem. 2009 Jul 9;52(13):3881-91. doi: 10.1021/jm900242c.

Novel potent BRAF inhibitors: toward 1 nM compounds through optimization of the central phenyl ring.

Author information

1
The Institute of Cancer Research, UK Centre for Cancer Therapeutics, Sutton, Surrey SM2 5NG, United Kingdom.

Abstract

BRAF, a serine/threonine specific protein kinase that is part of the MAPK pathway and acts as a downstream effector of RAS, is a potential therapeutic target in melanoma. We have developed a series of small-molecule BRAF inhibitors based on a 1H-imidazo[4,5-b]pyridine-2(3H)-one scaffold (ring A) as the hinge binding moiety and a number of substituted phenyl rings C that interact with the allosteric binding site. The introduction of various groups on the central phenyl ring B combined with appropriate A- and C-ring modifications afford very potent compounds that inhibit (V600E)BRAF kinase activity in vitro and oncogenic BRAF signaling in melanoma cells. Substitution on the central phenyl ring of a 3-fluoro, a naphthyl, or a 3-thiomethyl group improves activity to yield compounds with an IC(50) of 1 nM for purified (V600E)BRAF and nanomolar activity in cells.

PMID:
19473026
DOI:
10.1021/jm900242c
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center