Rheault Tara R, Stellwagen John C, Adjabeng George M, Hornberger Keith R, Petrov Kimberly G, Waterson Alex G, Dickerson Scott H, Mook Robert A, Laquerre Sylvie G, King Alastair J, Rossanese Olivia W, Arnone Marc R, Smitheman Kimberly N, Kane-Carson Laurie S, Han Chao, Moorthy Ganesh S, Moss Katherine G, Uehling David E
Oncology R&D Medicinal Chemistry, GlaxoSmithKline , Research Triangle Park , North Carolina 27709, United States.
Computational and Structural Chemistry, GlaxoSmithKline , Research Triangle Park, North Carolina 27709, United States.
ACS Med Chem Lett. 2013 Feb 7;4(3):358-62. doi: 10.1021/ml4000063. eCollection 2013 Mar 14.
Hyperactive signaling of the MAP kinase pathway resulting from the constitutively active B-Raf(V600E) mutated enzyme has been observed in a number of human tumors, including melanomas. Herein we report the discovery and biological evaluation of GSK2118436, a selective inhibitor of Raf kinases with potent in vitro activity in oncogenic B-Raf-driven melanoma and colorectal carcinoma cells and robust in vivo antitumor and pharmacodynamic activity in mouse models of B-Raf(V600E) human melanoma. GSK2118436 was identified as a development candidate, and early clinical results have shown significant activity in patients with B-Raf mutant melanoma.
在包括黑色素瘤在内的许多人类肿瘤中，已观察到由组成型活性B-Raf（V600E）突变酶导致的丝裂原活化蛋白激酶（MAP）途径的过度活跃信号传导。在此，我们报告了GSK2118436的发现及生物学评估，它是一种Raf激酶的选择性抑制剂，在致癌性B-Raf驱动的黑色素瘤和结肠癌细胞中具有强大的体外活性，并且在B-Raf（V600E）人类黑色素瘤小鼠模型中具有强大的体内抗肿瘤和药效学活性。GSK2118436被确定为一个开发候选药物，早期临床结果显示其对B-Raf突变黑色素瘤患者具有显著活性。
