title: Novel potent BRAF inhibitors: toward 1 nM compounds through optimization of the central phenyl ring.
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.
authors.affiliation: The Institute of Cancer Research, UK Centre for Cancer Therapeutics, Sutton, Surrey SM2 5NG, United Kingdom.
authors.forename: Delphine
authors.initials: D
authors.lastname: Ménard
authors.forename: Ion
authors.initials: I
authors.lastname: Niculescu-Duvaz
authors.forename: Harmen P
authors.initials: HP
authors.lastname: Dijkstra
authors.forename: Dan
authors.initials: D
authors.lastname: Niculescu-Duvaz
authors.forename: Bart M J M
authors.initials: BM
authors.lastname: Suijkerbuijk
authors.forename: Alfonso
authors.initials: A
authors.lastname: Zambon
authors.forename: Arnaud
authors.initials: A
authors.lastname: Nourry
authors.forename: Esteban
authors.initials: E
authors.lastname: Roman
authors.forename: Lawrence
authors.initials: L
authors.lastname: Davies
authors.forename: Helen A
authors.initials: HA
authors.lastname: Manne
authors.forename: Frank
authors.initials: F
authors.lastname: Friedlos
authors.forename: Ruth
authors.initials: R
authors.lastname: Kirk
authors.forename: Steven
authors.initials: S
authors.lastname: Whittaker
authors.forename: Adrian
authors.initials: A
authors.lastname: Gill
authors.forename: Richard D
authors.initials: RD
authors.lastname: Taylor
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Springer
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D010636:Phenols; D011725:Pyridines; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf