title: Structure-based design of high-affinity macrocyclic peptidomimetics to block the menin-mixed lineage leukemia 1 (MLL1) protein-protein interaction.
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.
authors.affiliation: Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan , 1500 E. Medical Center Drive, Ann Arbor, Michigan 48109-0934, USA.
authors.forename: Haibin
authors.initials: H
authors.lastname: Zhou
authors.forename: Liu
authors.initials: L
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.forename: Denzil
authors.initials: D
authors.lastname: Bernard
authors.forename: Hacer
authors.initials: H
authors.lastname: Karatas
authors.forename: Alexandro
authors.initials: A
authors.lastname: Navarro
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D011495:Histone-Lysine N-Methyltransferase; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C497422:KMT2A protein, human; C105373:MEN1 protein, human; D047028:Macrocyclic Compounds; D057786:Peptidomimetics; D011518:Proto-Oncogene Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase