Chemmedchem 2011-05-02

Discovery and development of thiazolo[3,2-a]pyrimidinone derivatives as general inhibitors of Bcl-2 family proteins.

Bingcheng Zhou, Xun Li, Yan Li, Yaochun Xu, Zhengxi Zhang, Mi Zhou, Xinglong Zhang, Zhen Liu, Jiahai Zhou, Chunyang Cao, Biao Yu, Renxiao Wang

Index: ChemMedChem 6 , 904, (2011)

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Abstract

A class of compounds with a common thiazolo[3,2-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-x(L) protein was further confirmed by (15) N-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-x(L), Bcl-2, and Mcl-1 with inhibition constants (K(i)) of 17, 534, and 200 nM, respectively.Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.