Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
Bioorg Med Chem Lett. 2014 Apr 15;24(8):1923-7. doi: 10.1016/j.bmcl.2014.03.007. Epub 2014 Mar 13.
Herein we describe the design of a novel series of ATP competitive B-Raf inhibitors via structure-based methods. These 3-N-methylquinazoline-4(3H)-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 16, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies. Our work also demonstrates that by replacing an aryl amide with an aryl sulfonamide, a multikinase inhibitor such as AZ-628, can be converted to a selective B-Raf inhibitor, a finding that should have broad application in kinase drug discovery.
在此，我们通过基于结构的方法描述了一系列新型的 ATP 竞争性 B-Raf 抑制剂的设计。这些基于 3-N-甲基喹唑啉-4(3H)-酮的抑制剂表现出优异的细胞效力和显著的 B-Raf 选择性。通过优化，确定了化合物 16，它是一种具有良好药代动力学性质和在异种移植研究中具有强大肿瘤生长抑制作用的有效、选择性和可口服的试剂。我们的工作还表明，通过用芳基磺酰胺替代芳基酰胺，可以将多激酶抑制剂（如 AZ-628）转化为选择性 B-Raf 抑制剂，这一发现应该在激酶药物发现中具有广泛的应用。
