2. Academic Validation
  3. Design and synthesis of benzylpiperidine inhibitors targeting the menin-MLL1 interface

Design and synthesis of benzylpiperidine inhibitors targeting the menin-MLL1 interface

  • Bioorg Med Chem Lett. 2016 Sep 15;26(18):4472-4476. doi: 10.1016/j.bmcl.2016.07.074.
Jing Ren 1,  Wei Xu 2,  Le Tang 3,  Minbo Su 4,  Danqi Chen 3,  Yue-Lei Chen 1,  Yi Zang 4,  Jia Li 2,  Jingkang Shen 1,  Yubo Zhou 5,  Bing Xiong 6
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
  • 4 The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, PR China.
  • 5 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.
  • 6 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.
PMID: 27528435 DOI: 10.1016/j.bmcl.2016.07.074
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.

Keywords

Inhibitor; MLL1; Menin; Mixed lineage leukemia; SAR.

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