title: Discovery and development of thiazolo[3,2-a]pyrimidinone derivatives as general inhibitors of Bcl-2 family proteins.
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.
authors.affiliation: State Key Laboratory of Bioorganic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, P R China.
authors.forename: Bingcheng
authors.initials: B
authors.lastname: Zhou
authors.forename: Xun
authors.initials: X
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Yaochun
authors.initials: Y
authors.lastname: Xu
authors.forename: Zhengxi
authors.initials: Z
authors.lastname: Zhang
authors.forename: Mi
authors.initials: M
authors.lastname: Zhou
authors.forename: Xinglong
authors.initials: X
authors.lastname: Zhang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Jiahai
authors.initials: J
authors.lastname: Zhou
authors.forename: Chunyang
authors.initials: C
authors.lastname: Cao
authors.forename: Biao
authors.initials: B
authors.lastname: Yu
authors.forename: Renxiao
authors.initials: R
authors.lastname: Wang
mesh_terms: D001665:Binding Sites; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D056004:Molecular Dynamics Simulation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C560361:(Z)-ethyl 2-((1-(biphenyl-4-ylmethyl)indol-3-yl) methylene)-7-methyl-3-oxo-5-phenylthiazolo(3,2-a)pyrimidine-6-carboxylate; D001713:Biphenyl Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D013844:Thiazoles; C039201:thiazolo(3,2-a)perimidine