title: Potent and selective aminopyrimidine-based B-Raf inhibitors with favorable physicochemical and pharmacokinetic properties.
abstract: Recent clinical data provided proof-of-concept for selective B-Raf inhibitors in treatment of B-Raf(V600E) mutant melanoma. Pyrazolopyridine-type B-Raf inhibitors previously described by the authors are potent and selective but exhibit low solubility requiring the use of amorphous dispersion-based formulation for achieving efficacious drug exposures. Through structure-based design, we discovered a new class of highly potent aminopyrimidine-based B-Raf inhibitors with improved solubility and pharmacokinetic profiles. The hinge binding moiety possesses a basic center imparting high solubility at gastric pH, addressing the dissolution limitation observed with our previous series. In our search for an optimal linker-hinge binding moiety system, amide-linked thieno[3,2-d]pyrimidine analogues 32 and 35 (G945), molecules with desirable physicochemical properties, emerged as lead compounds with strong efficacy in a B-Raf(V600E) mutant mouse xenograft model. Synthesis, SAR, lead selection, and evaluation of key compounds in animal studies will be described.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
authors.forename: Simon
authors.initials: S
authors.lastname: Mathieu
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Gradl
authors.forename: Li
authors.initials: L
authors.lastname: Ren
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Wen
authors.forename: Ignacio
authors.initials: I
authors.lastname: Aliagas
authors.forename: Janet
authors.initials: J
authors.lastname: Gunzner-Toste
authors.forename: Wendy
authors.initials: W
authors.lastname: Lee
authors.forename: Rebecca
authors.initials: R
authors.lastname: Pulk
authors.forename: Guiling
authors.initials: G
authors.lastname: Zhao
authors.forename: Bruno
authors.initials: B
authors.lastname: Alicke
authors.forename: Jason W
authors.initials: JW
authors.lastname: Boggs
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Buckmelter
authors.forename: Edna F
authors.initials: EF
authors.lastname: Choo
authors.forename: Victoria
authors.initials: V
authors.lastname: Dinkel
authors.forename: Susan L
authors.initials: SL
authors.lastname: Gloor
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gould
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Hansen
authors.forename: Gregg
authors.initials: G
authors.lastname: Hastings
authors.forename: Georgia
authors.initials: G
authors.lastname: Hatzivassiliou
authors.forename: Ellen R
authors.initials: ER
authors.lastname: Laird
authors.forename: David
authors.initials: D
authors.lastname: Moreno
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Ran
authors.forename: Walter C
authors.initials: WC
authors.lastname: Voegtli
authors.forename: Steve
authors.initials: S
authors.lastname: Wenglowsky
authors.forename: Jonas
authors.initials: J
authors.lastname: Grina
authors.forename: Joachim
authors.initials: J
authors.lastname: Rudolph
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D011799:Quinazolines; D013876:Thiophenes; D048493:Proto-Oncogene Proteins B-raf