期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 14, 页码 10333-10349出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00789
关键词
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资金
- National Institutes of Health/National Cancer Institute [R01 CA208267]
- Prostate Cancer Foundation
- National Cancer Institutes, NIH [P30 CA046592]
- Agios Pharmaceuticals
- U.S. DOE [DE-AC02-06CH11357]
- Michigan Economic Development Corporation
- Michigan Technology TriCorridor [085P1000817]
M-1121 is a covalent and orally active inhibitor that achieves complete and persistent tumor regression by targeting the menin-MLL protein interaction and driving dose-dependent down-regulation of key genes in MLL-rearranged leukemia cell lines. It shows potent antitumor activity in vivo with tumor regressions observed at tolerated doses. These findings support the development of an orally active covalent menin inhibitor as a new therapy for MLLr leukemia.
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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