1309220-95-8Relevant articles and documents
Discovery and development of thiazolo[3,2-a]pyrimidinone derivatives as general inhibitors of Bcl-2 family proteins
Zhou, Bingcheng,Li, Xun,Li, Yan,Xu, Yaochun,Zhang, Zhengxi,Zhou, Mi,Zhang, Xinglong,Liu, Zhen,Zhou, Jiahai,Cao, Chunyang,Yu, Biao,Wang, Renxiao
, p. 904 - 921 (2012/01/06)
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-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 200nM, respectively. Keeping it in the family! Compounds with a common thiazolo[3,2-a]pyrimidinone motif have been developed as general inhibitors of Bcl-2 family proteins. The lead compound BCL-LZH-01 (shown in green) was identified as a Bcl-xL protein binder in a random screening using a fluorescence polarization-based binding assay, and further confirmed by 15N-HSQC NMR experiments. Of the 42 derivative described, BCL-LZH-40 (shown in blue) is the most potent, inhibiting the binding of BH3 peptides to Bcl-xL, Bcl-2, and Mcl-1 with inhibition constants (Ki) of 17, 534, and 200nM, respectively.
