期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 3, 页码 1113-1123出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm3015298
关键词
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资金
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
Menin is an essential oncogenic cofactor for mixed lineage leukemia 1 (MLL1)-mediated leukemogenesis through its direct interaction with MLL1. Targeting the menin-MLL1 protein-protein interaction represents a promising strategy to block MLL1-mediated leukemogenesis. Employing a structure-based approach and starting from a linear MLL1 octapeptide, we have designed a class of potent macrocyclic peptidomimetic inhibitors of the menin-MLL1 interaction. The most potent macrocyclic peptidomimetic (MCP-1), 34, binds to menin with a K-i value of 4.7 nM and is >600 times more potent than the corresponding acyclic peptide. Compound 34 is also less peptide-like and has a lower molecular weight than the initial MLL1 peptide. Therefore, compound 34 serves as a promising lead structure for the design of potent and cell-permeable inhibitors of the menin-MLLI interaction.
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