Oncology iMED, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
J Med Chem. 2013 Mar 14;56(5):1996-2015. doi: 10.1021/jm301658d. Epub 2013 Feb 27.
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.
B-Raf 是一种有吸引力的抗癌治疗靶点，小分子 B-Raf 抑制剂的开发为转移性黑色素瘤患者带来了新的治疗方法。我们发现了一类新型小分子，可在体外和体内抑制突变型 B-Raf(V600E)激酶活性。本文介绍了该系列化合物的构效关系研究，并努力提高其细胞效力、溶解度和药代动力学特性。化合物在体外选择性抑制 B-Raf(V600E)，在突变型 B-Raf(V600E)细胞系中表现出优先的抗增殖活性，并在激酶谱中对其他激酶表现出选择性。该系列的一些化合物在可耐受的剂量下可抑制 B-Raf(V600E) A375 异种移植瘤的生长。此外，本文还描述了所描述的氨基喹唑啉类化合物在体外非突变型 B-Raf 细胞系中可显示 pERK 升高。
