作为CBP/P300溴结构域抑制剂的联芳基系列的设计与合成。
Design and synthesis of a biaryl series as inhibitors for the bromodomains of CBP/P300.
作者信息
Lai Kwong Wah, Romero F Anthony, Tsui Vickie, Beresini Maureen H, de Leon Boenig Gladys, Bronner Sarah M, Chen Kevin, Chen Zhongguo, Choo Edna F, Crawford Terry D, Cyr Patrick, Kaufman Susan, Li Yingjie, Liao Jiangpeng, Liu Wenfeng, Ly Justin, Murray Jeremy, Shen Weichao, Wai John, Wang Fei, Zhu Caicai, Zhu Xiaoyu, Magnuson Steven
机构信息
WuXi AppTec Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
出版信息
Bioorg Med Chem Lett. 2018 Jan 1;28(1):15-23. doi: 10.1016/j.bmcl.2017.11.025. Epub 2017 Nov 14.
A novel, potent, and orally bioavailable inhibitor of the bromodomain of CBP, compound 35 (GNE-207), has been identified through SAR investigations focused on optimizing al bicyclic heteroarene to replace the aniline present in the published GNE-272 series. Compound 35 has excellent CBP potency (CBP IC = 1 nM, MYC EC = 18 nM), a selectively index of >2500-fold against BRD4(1), and exhibits a good pharmacokinetic profile.
通过以优化双环杂芳烃取代已发表的GNE - 272系列中存在的苯胺为重点的构效关系研究，已鉴定出一种新型、强效且口服生物可利用的CBP溴结构域抑制剂，即化合物35（GNE - 207）。化合物35具有出色的CBP活性（CBP IC = 1 nM，MYC EC = 18 nM），对BRD4(1)的选择性指数大于2500倍，并且具有良好的药代动力学特征。
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