基于吲哚的EZH2抑制剂的发现、设计与合成。
Discovery, design, and synthesis of indole-based EZH2 inhibitors.
作者信息
Gehling Victor S, Vaswani Rishi G, Nasveschuk Christopher G, Duplessis Martin, Iyer Priyadarshini, Balasubramanian Srividya, Zhao Feng, Good Andrew C, Campbell Robert, Lee Christina, Dakin Les A, Cook Andrew S, Gagnon Alexandre, Harmange Jean-Christophe, Audia James E, Cummings Richard T, Normant Emmanuel, Trojer Patrick, Albrecht Brian K
机构信息
Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
出版信息
Bioorg Med Chem Lett. 2015 Sep 1;25(17):3644-9. doi: 10.1016/j.bmcl.2015.06.056. Epub 2015 Jun 19.
The discovery and optimization of a series of small molecule EZH2 inhibitors is described. Starting from dimethylpyridone HTS hit (2), a series of indole-based EZH2 inhibitors were identified. Biochemical potency and microsomal stability were optimized during these studies and afforded compound 22. This compound demonstrates nanomolar levels of biochemical potency (IC50=0.002 μM), cellular potency (EC50=0.080 μM), and afforded tumor regression when dosed (200 mpk SC BID) in an EZH2 dependent tumor xenograft model.
本文描述了一系列小分子EZH2抑制剂的发现与优化过程。从二甲基吡啶酮高通量筛选活性化合物（2）出发，鉴定出了一系列基于吲哚的EZH2抑制剂。在这些研究过程中，对生化活性和微粒体稳定性进行了优化，得到了化合物22。该化合物表现出纳摩尔级别的生化活性（IC50 = 0.002 μM）、细胞活性（EC50 = 0.080 μM），并且在EZH2依赖性肿瘤异种移植模型中给药（200 mpk皮下注射，每日两次）时可使肿瘤消退。
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