title: Discovery and optimization of a novel series of potent mutant B-Raf(V600E) selective kinase inhibitors.
abstract: B-Raf represents an attractive target for anticancer therapy and the development of small molecule B-Raf inhibitors has delivered new therapies for metastatic melanoma patients. We have discovered a novel class of small molecules that inhibit mutant B-Raf(V600E) kinase activity both in vitro and in vivo. Investigations into the structure-activity relationships of the series are presented along with efforts to improve upon the cellular potency, solubility, and pharmacokinetic profile. Compounds selectively inhibited B-Raf(V600E) in vitro and showed preferential antiproliferative activity in mutant B-Raf(V600E) cell lines and exhibited selectivity in a kinase panel against other kinases. Examples from this series inhibit growth of a B-Raf(V600E) A375 xenograft in vivo at a well-tolerated dose. In addition, aminoquinazolines described herein were shown to display pERK elevation in nonmutant B-Raf cell lines in vitro.
authors: Oncology iMED, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States. melissa.vasbinder@astrazeneca.com
authors: Melissa M
authors: MM
authors: Vasbinder
authors: Brian
authors: B
authors: Aquila
authors: Martin
authors: M
authors: Augustin
authors: Huawei
authors: H
authors: Chen
authors: Tony
authors: T
authors: Cheung
authors: Donald
authors: D
authors: Cook
authors: Lisa
authors: L
authors: Drew
authors: Benjamin P
authors: BP
authors: Fauber
authors: Steve
authors: S
authors: Glossop
authors: Michael
authors: M
authors: Grondine
authors: Edward
authors: E
authors: Hennessy
authors: Jeffrey
authors: J
authors: Johannes
authors: Stephen
authors: S
authors: Lee
authors: Paul
authors: P
authors: Lyne
authors: Mario
authors: M
authors: Mörtl
authors: Charles
authors: C
authors: Omer
authors: Sangeetha
authors: S
authors: Palakurthi
authors: Timothy
authors: T
authors: Pontz
authors: Jon
authors: J
authors: Read
authors: Li
authors: L
authors: Sha
authors: Minhui
authors: M
authors: Shen
authors: Stefan
authors: S
authors: Steinbacher
authors: Haixia
authors: H
authors: Wang
authors: Allan
authors: A
authors: Wu
authors: Minwei
authors: M
authors: Ye
mesh_terms: D000818:Animals; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D011799:Quinazolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D048493:Proto-Oncogene Proteins B-raf