2. Academic Validation
  3. Design and development of a series of 4-(piperazin-1-yl)pyrimidines as irreversible menin inhibitors

Design and development of a series of 4-(piperazin-1-yl)pyrimidines as irreversible menin inhibitors

  • Eur J Med Chem. 2024 Sep 30:280:116918. doi: 10.1016/j.ejmech.2024.116918.
Menglan Luo 1,  Yunfei Ye 2,  Lu Tang 3,  Weijuan Kan 4,  Lin Chen 4,  Cong Li 4,  Li Sheng 4,  Yubo Zhou 2,  Jia Li 5,  Bing Xiong 6,  Hanlin Wang 7,  Danqi Chen 8
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; Department of Chemistry, College of Sciences, Shanghai University, 99 Shangda Road, Shanghai, 200444, China.
  • 2 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing, 100049, China.
  • 3 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing, 100049, China.
  • 4 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.
  • 5 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing, 100049, China. Electronic address: jli@simm.ac.cn.
  • 6 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing, 100049, China. Electronic address: bxiong@simm.ac.cn.
  • 7 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing, 100049, China. Electronic address: wanghanlin@simm.ac.cn.
  • 8 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing, 100049, China. Electronic address: dqchen@simm.ac.cn.
PMID: 39366253 DOI: 10.1016/j.ejmech.2024.116918
Abstract

The interaction between menin and MLL1 protein plays an important role in AML with MLL rearrangement and NPM1 mutation. Blocking the formation of menin-MLL complex can inhibit proliferation and induce differentiation in these Cancer subtypes. In development of Anticancer drugs, irreversible inhibitors are gaining spotlight as they may have better activities than the reversible analogs. Therefore, we designed and developed a novel series of covalent menin inhibitors. Among these compounds, 37 emerges as a selective and potent inhibitor of MLL fusion protein-expressing leukemic cells. The cellular study indicates 37 has a distinct mechanism of action, in both reducing menin protein levels and downregulating MEN1 transcription. This effect of 37 is not involved in proteasomal degradation, and may directly affect the synthesis of menin protein, which offers a significant advantage in addressing acquired resistance to menin inhibitors. Further study showed that compound 37 has prolonged anti-leukemic action and exhibits promising in vivo efficacy, making it a valuable probe for further menin-MLL interaction studies.

Keywords

Antitumor; Covalent inhibitor; Degradation; Menin.

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