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

Jing Ren; Wei Xu; Le Tang; Minbo Su; Danqi Chen; Yue-Lei Chen; Yi Zang; Jia Li; Jingkang Shen; Yubo Zhou; Bing Xiong

doi:10.1016/j.bmcl.2016.07.074

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. Epub 2016 Aug 2.

Authors

Jing Ren¹, Wei Xu², Le Tang³, Minbo Su⁴, Danqi Chen³, Yue-Lei Chen¹, Yi Zang⁴, Jia Li², Jingkang Shen¹, Yubo Zhou⁵, Bing Xiong⁶

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.

MeSH terms

Cell Line, Tumor
Crystallography, X-Ray
Drug Design
Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
Histone-Lysine N-Methyltransferase / chemistry
Humans
Molecular Docking Simulation
Myeloid-Lymphoid Leukemia Protein / antagonists & inhibitors*
Myeloid-Lymphoid Leukemia Protein / chemistry
Piperidines / chemical synthesis
Piperidines / chemistry*
Piperidines / pharmacology*
Structure-Activity Relationship

Substances

KMT2A protein, human
Piperidines
Myeloid-Lymphoid Leukemia Protein
Histone-Lysine N-Methyltransferase