title: Novel soluble myeloid cell leukemia sequence 1 (Mcl-1) inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g) developed using a fragment-based approach.
abstract: Based on a known nanomolar Bcl-2 homology domain 3 (BH3) mimetic 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b] pyrrole-9-carbonitrile (S1, MW: 331), we applied a fragment-based approach to obtain BH3 mimetics with improved affinity and improved solubility in a water-ethanol (9:1) cosolvent. After the deconstruction of 1 (S1), we obtained fragment cyanoacetamide (4), which was determined to be a ligand efficiency (LE) hot part. After a rational optimization through fragment evolution beginning with fragment 4, a smaller Mcl-1 inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g, MW: 288) with a 6-fold increase in affinity compared to 1 was obtained, as predicted by our optimization curve and identified by Mcl-1 protein nuclear magnetic resonance (NMR).
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, No. 2, Linggong Road, Dalian 116012, People's Republic of China. zczhang@dlut.edu.cn
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhang
authors.forename: Ting
authors.initials: T
authors.lastname: Song
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Li
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Wu
authors.forename: Yingang
authors.initials: Y
authors.lastname: Feng
authors.forename: Feibo
authors.initials: F
authors.lastname: Xie
authors.forename: Chengwu
authors.initials: C
authors.lastname: Liu
authors.forename: Jianquan
authors.initials: J
authors.lastname: Qin
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chen
mesh_terms: D000181:Acrylonitrile / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001596:Benzylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D032701:Biomimetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011485:Protein Binding / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D012995:Solubility / Q000187:drug effects; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: C583879:(E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile; D001596:Benzylamines; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D000181:Acrylonitrile