title: Probing the difference between BH3 groove of Mcl-1 and Bcl-2 protein: Implications for dual inhibitors design.
abstract: Based on our previous discovery of a dual inhibitor of Mcl-1 and Bcl-2, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (1, S1), and guided by structure insight of 1 complex with Mcl-1 and Bcl-2, we exploited the spatial orientation of BH3 groove of the two proteins by a series of analogues of 1. These analogues contain substitutes with various steric hindrance designed to explore the width and length of the p2 pocket. The structure-activity relationships (SARs) studies together with docking studies and cell-based assays proved that the p2 pocket of Mcl-1 is relatively wider and shorter than that of Bcl-2. A novel dual inhibitor 6 was obtained based on these new findings that it exhibited nanomalar affinities toward Mcl-1 and Bcl-2, as well as nanomalar cytotoxicity activity against multiple cancer cell lines.
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian 116012, People's Republic of China. zczhang@dlut.edu.cn
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhang
authors.forename: Hongna
authors.initials: H
authors.lastname: Yang
authors.forename: Guiye
authors.initials: G
authors.lastname: Wu
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Li
authors.forename: Ting
authors.initials: T
authors.lastname: Song
authors.forename: Xiang Qian
authors.initials: XQ
authors.lastname: Li
mesh_terms: D000073:Acenaphthenes; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005454:Fluorescence Polarization; D006801:Humans; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015335:Molecular Probes; D009025:Morpholines / Q000737:chemistry* / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: C557101:8-oxo-3-thiomorpholin-4-yl-8H-acenaphtho(1,2-b)pyrrole-9-carbonitrile; D000073:Acenaphthenes; D015335:Molecular Probes; D009025:Morpholines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles