Discovery and development of thiazolo[3,2-a]pyrimidinone derivatives as general inhibitors of Bcl-2 family proteins |
| |
| Authors: | Zhou Bingcheng Li Xun Li Yan Xu Yaochun Zhang Zhengxi Zhou Mi Zhang Xinglong Liu Zhen Zhou Jiahai Cao Chunyang Yu Biao Wang Renxiao |
| |
| Affiliation: | State Key Laboratory of Bioorganic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, P R China. |
| |
| Abstract: | A class of compounds with a common thiazolo3,2‐a]pyrimidinone motif has been developed as general inhibitors of Bcl‐2 family proteins. The lead compound was originally identified in a random screening of a small compound library using a fluorescence polarization‐based competitive binding assay. Its binding to the Bcl‐xL protein was further confirmed by 15N‐HSQC NMR experiments. Structural modifications on the lead compound were guided by the outcomes of molecular modeling studies. Among the 42 compounds obtained, a number of them exhibited much improved binding affinities to Bcl‐2 family proteins as compared to the lead compound. The most potent compound, BCL‐LZH‐ 40 , inhibited the binding of BH3 peptides to Bcl‐xL, Bcl‐2, and Mcl‐1 with inhibition constants (Ki) of 17, 534, and 200 nM , respectively. |
| |
| Keywords: | Bcl‐2 family proteins inhibitors protein–protein interactions small molecules structure‐based drug design |
| 本文献已被 PubMed 等数据库收录！ |
|
