Structure-based design of high-affinity macrocyclic peptidomimetics to block the menin-mixed lineage leukemia 1
Haibin Zhou1, Liu Liu, Jing Huang
1Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan , 1500 E. Medical Center Drive, Ann Arbor, Michigan 48109-0934, USA.
Abstract:
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-MLL1 interaction.
