BET 溴结构域的甲基吡咯抑制剂。
Methylpyrrole inhibitors of BET bromodomains.
作者信息
Hasvold Lisa A, Sheppard George S, Wang Le, Fidanze Steven D, Liu Dachun, Pratt John K, Mantei Robert A, Wada Carol K, Hubbard Robbert, Shen Yu, Lin Xiaoyu, Huang Xiaoli, Warder Scott E, Wilcox Denise, Li Leiming, Buchanan F Greg, Smithee Lauren, Albert Daniel H, Magoc Terrance J, Park Chang H, Petros Andrew M, Panchal Sanjay C, Sun Chaohong, Kovar Peter, Soni Nirupama B, Elmore Steven W, Kati Warren M, McDaniel Keith F
机构信息
AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
出版信息
Bioorg Med Chem Lett. 2017 May 15;27(10):2225-2233. doi: 10.1016/j.bmcl.2017.02.057. Epub 2017 Feb 24.
An NMR fragment screen for binders to the bromodomains of BRD4 identified 2-methyl-3-ketopyrroles 1 and 2. Elaboration of these fragments guided by structure-based design provided lead molecules with significant activity in a mouse tumor model. Further modifications to the methylpyrrole core provided compounds with improved properties and enhanced activity in a mouse model of multiple myeloma.
一项针对与BRD4溴结构域结合剂的核磁共振片段筛选鉴定出了2-甲基-3-酮基吡咯1和2。在基于结构的设计指导下对这些片段进行优化，得到了在小鼠肿瘤模型中具有显著活性的先导分子。对甲基吡咯核心进行进一步修饰，得到了在多发性骨髓瘤小鼠模型中具有改善性质和增强活性的化合物。
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