title: Pyrazolopyridine inhibitors of B-Raf(V600E). Part 4: rational design and kinase selectivity profile of cell potent type II inhibitors.
abstract: Cell potent inhibitors of B-Raf(V600E) that bind to the kinase in the DFG-out conformation are reported. These compounds utilize the hinge-binding group and lipophilic linker from a previously disclosed series of B-Raf(V600E) inhibitors that bind to the kinase in an atypical DFG-in, αC-helix-out conformation. This new series demonstrates that DFG-out kinase inhibitors can be rationally designed from related inhibitors which utilize an unconventional binding mode. Kinase selectivity profiles are compared. The pattern of kinase selectivity was found to be determined by the feature of the inhibitor which extends into the back pocket of the kinase and leads to the kinase conformation, rather than by the hinge-binding group or other minor modifications.
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Wenglowsky
authors.forename: David
authors.initials: D
authors.lastname: Moreno
authors.forename: Ellen R
authors.initials: ER
authors.lastname: Laird
authors.forename: Susan L
authors.initials: SL
authors.lastname: Gloor
authors.forename: Li
authors.initials: L
authors.lastname: Ren
authors.forename: Tyler
authors.initials: T
authors.lastname: Risom
authors.forename: Joachim
authors.initials: J
authors.lastname: Rudolph
authors.forename: Hillary L
authors.initials: HL
authors.lastname: Sturgis
authors.forename: Walter C
authors.initials: WC
authors.lastname: Voegtli
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004355:Drug Stability; D006801:Humans; D051379:Mice; D008861:Microsomes / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine; D048493:Proto-Oncogene Proteins B-raf