Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, United States.
Bioorg Med Chem Lett. 2010 Nov 15;20(22):6560-4. doi: 10.1016/j.bmcl.2010.09.046. Epub 2010 Sep 21.
High-throughput screening of 66,000 compounds using competitive binding of peptides comprising the BH3 domain to anti-apoptotic Bfl-1 led to the identification of 14 validated 'hits' as inhibitors of Bfl-1. N-Aryl maleimide 1 was among the validated 'hits'. A chemical library encompassing over 280 analogs of 1 was prepared following a two-step synthesis. Structure-activity studies for inhibition of Bfl-1 by analogs of N-aryl maleimide 1 revealed a preference for electron-withdrawing substituents in the N-aryl ring and hydrophilic amines appended to the maleimide core. Inhibitors of Bfl-1 are potential development candidates for anti-cancer therapeutics.
采用包含 BH3 结构域的肽与抗凋亡蛋白 Bfl-1 的竞争结合对 66000 种化合物进行高通量筛选，鉴定出 14 种有效的 Bfl-1 抑制剂，即“命中化合物”。N-芳基马来酰亚胺 1 就是其中之一。在两步合成法的基础上，我们制备了包含超过 280 种 N-芳基马来酰亚胺 1 类似物的化学文库。通过对 N-芳基马来酰亚胺 1 的类似物抑制 Bfl-1 的结构活性研究，发现 N-芳基环上带有吸电子取代基和连接在马来酰亚胺核心上的亲水胺的类似物具有更好的抑制效果。Bfl-1 的抑制剂是潜在的抗癌治疗药物开发候选物。
