Novel potent BRAF inhibitors: toward 1 nM compounds through optimization of the central phenyl ring.
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.
Ménard
Delphine
D
The Institute of Cancer Research, UK Centre for Cancer Therapeutics, Sutton, Surrey SM2 5NG, United Kingdom.
Niculescu-Duvaz
Ion
I
Dijkstra
Harmen P
HP
Niculescu-Duvaz
Dan
D
Suijkerbuijk
Bart M J M
BM
Zambon
Alfonso
A
Nourry
Arnaud
A
Roman
Esteban
E
Davies
Lawrence
L
Manne
Helen A
HA
Friedlos
Frank
F
Kirk
Ruth
R
Whittaker
Steven
S
Gill
Adrian
A
Taylor
Richard D
RD
Marais
Richard
R
Springer
Caroline J
CJ
D000495:Allosteric Site; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008545:Melanoma / Q000188:drug therapy; D020125:Mutation, Missense; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D010636:Phenols; D011725:Pyridines; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf