2. Academic Validation
  3. Discovery of M-1121 as an Orally Active Covalent Inhibitor of Menin-MLL Interaction Capable of Achieving Complete and Long-Lasting Tumor Regression

Discovery of M-1121 as an Orally Active Covalent Inhibitor of Menin-MLL Interaction Capable of Achieving Complete and Long-Lasting Tumor Regression

  • J Med Chem. 2021 Jul 22;64(14):10333-10349. doi: 10.1021/acs.jmedchem.1c00789.
Meng Zhang 1 2,  Angelo Aguilar 1 2,  Shilin Xu 1 2,  Liyue Huang 1 2,  Krishnapriya Chinnaswamy 3,  Taryn Sleger 4,  Bo Wang 4,  Stefan Gross 4,  Brandon N Nicolay 4,  Sebastien Ronseaux 4,  Kaitlin Harvey 1 2,  Yu Wang 1 2,  Donna McEachern 1 2,  Paul D Kirchhoff 1 2,  Zhaomin Liu 1 2,  Jeanne Stuckey 3,  Adriana E Tron 4,  Tao Liu 4,  Shaomeng Wang 1 2 5 6
Affiliations

Affiliations

  • 1 Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3 Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4 Agios Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, United States.
  • 5 Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 6 Department of Medicinal Chemistry, Medical School, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 34196551 DOI: 10.1021/acs.jmedchem.1c00789
Abstract

Targeting the menin-MLL protein-protein interaction is being pursued as a new therapeutic strategy for the treatment of acute leukemia carrying MLL-rearrangements (MLLr leukemia). Herein, we report M-1121, a covalent and orally active inhibitor of the menin-MLL interaction capable of achieving complete and persistent tumor regression. M-1121 establishes covalent interactions with Cysteine 329 located in the MLL binding pocket of menin and potently inhibits growth of acute leukemia cell lines carrying MLL translocations with no activity in cell lines with wild-type MLL. Consistent with the mechanism of action, M-1121 drives dose-dependent down-regulation of HOXA9 and MEIS1 gene expression in the MLL-rearranged MV4;11 leukemia cell line. M-1121 is orally bioavailable and shows potent antitumor activity in vivo with tumor regressions observed at tolerated doses in the MV4;11 subcutaneous and disseminated models of MLL-rearranged leukemia. Together, our findings support development of an orally active covalent menin inhibitor as a new therapy for MLLr leukemia.

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