发现口服生物可利用的配体高效喹唑啉二酮作为强效和选择性端锚聚合酶抑制剂。
Discovery of Orally Bioavailable Ligand Efficient Quinazolindiones as Potent and Selective Tankyrases Inhibitors.
作者信息
Qin Donghui, Lin Xiaojuan, Liu Zhi, Chen Yan, Zhang Zhiliu, Wu Chengde, Liu Linlin, Pan Yan, Laquerre Sylvie, Emery John, Fergusson Jeff, Roland Kimberly, Keenan Rick, Oliff Allen, Kumar Sanjay, Cheung Mui, Su Dai-Shi
机构信息
Virtual PoC DPU, Alternative Discovery and Development, IVIVT, Platform Technologies and Sciences, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
出版信息
ACS Med Chem Lett. 2021 May 13;12(6):1005-1010. doi: 10.1021/acsmedchemlett.1c00160. eCollection 2021 Jun 10.
We report herein the discovery of quinazolindiones as potent and selective tankyrase inhibitors. Elucidation of the structure-activity relationship of the lead compound led to truncated analogues that have good potency in cells, pharmacokinetic (PK) properties, and excellent selectivity. Compound exhibited excellent potencies in cells and proliferation studies, good selectivity, activities, and an excellent PK profile. Compound also inhibited H292 xenograft tumor growth in nude mice. The synthesis, biological, pharmacokinetic, efficacy studies, and safety profiles of compounds are presented.
我们在此报告喹唑啉二酮作为有效的选择性端锚聚合酶抑制剂的发现。对先导化合物构效关系的阐明产生了在细胞中具有良好效力、药代动力学（PK）特性和出色选择性的截短类似物。化合物在细胞和增殖研究中表现出优异的效力、良好的选择性、活性以及出色的药代动力学特征。化合物还抑制了裸鼠体内H292异种移植肿瘤的生长。本文介绍了这些化合物的合成、生物学、药代动力学、疗效研究及安全性概况。
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