title: Fragment-based design, synthesis, and biological evaluation of N-substituted-5-(4-isopropylthiophenol)-2-hydroxynicotinamide derivatives as novel Mcl-1 inhibitors.
abstract: We have previously reported a nanomolar inhibitor of antiapoptotic Mcl-1 protein, 3-thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1). S1 plays its function by binding to the BH3 groove of Mcl-1. Basing on this spacial structural characteristic, we developed a novel class of Mcl-1 inhibitor using fragment-based drug discovery approach. By dissecting S1, we identified the compound 4 with a 2-hydroxypyridine core as the starting fragment. In the following molecular growth, we used the ligand efficiency evaluation and fit quality score to assess the fragments. A novel potent compound, N-benzyl-5-(4-isopropylthiophenol)-2-hydroxyl nicotinamide (12c), which binds Mcl-1 with an IC(50) value of 54 nM was obtained. Compound 12c demonstrated a better aqueous solubility than S1.
authors: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, No.2 Linggong Road, Dalian 116012, PR China. zczhang@dlut.edu.cn
authors: Zhichao
authors: Z
authors: Zhang
authors: Chengwu
authors: C
authors: Liu
authors: Xiangqian
authors: X
authors: Li
authors: Ting
authors: T
authors: Song
authors: Zhiyong
authors: Z
authors: Wu
authors: Xiaomeng
authors: X
authors: Liang
authors: Yan
authors: Y
authors: Zhao
authors: Xiaoyun
authors: X
authors: Shen
authors: Hongbo
authors: H
authors: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009536:Niacinamide / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D009536:Niacinamide