title: Design and synthesis of benzylpiperidine inhibitors targeting the menin-MLL1 interface.
abstract: Menin is an essential oncogenic cofactor for mixed lineage leukemia (MLL)-mediated leukemogenesis, functioning through its direct interaction with MLL1 protein. Therefore, targeting the menin-MLL1 protein-protein interface represents a promising strategy to block MLL-mediated leukemogenesis. On the basis of co-crystal structure analysis, starting from thienopyrimidine chemotype, we have investigated the detailed structure-activity relationship of the piperazinyl-dihydrothiazole moiety. Several compounds were found with potent inhibitory activity against menin and better activities in cell-based experiments than MI-2-2. Molecular docking analysis revealed a less explored subpocket, which could be used for the design of new menin-MLL1 inhibitors.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ren
authors.affiliation: The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
authors.forename: Le
authors.initials: L
authors.lastname: Tang
authors.affiliation: The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, PR China.
authors.forename: Minbo
authors.initials: M
authors.lastname: Su
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
authors.forename: Danqi
authors.initials: D
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China.
authors.forename: Yue-Lei
authors.initials: YL
authors.lastname: Chen
authors.affiliation: The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zang
authors.affiliation: The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China.
authors.forename: Jingkang
authors.initials: J
authors.lastname: Shen
authors.affiliation: The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China. Electronic address: ybzhou@simm.ac.cn.
authors.forename: Yubo
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China. Electronic address: bxiong@simm.ac.cn.
authors.forename: Bing
authors.initials: B
authors.lastname: Xiong
mesh_terms: D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D062105:Molecular Docking Simulation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C497422:KMT2A protein, human; D010880:Piperidines; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase
keywords: Inhibitor; MLL1; Menin; Mixed lineage leukemia; SAR