Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein-Protein Interaction.
The structure-based design of M-525 as the first-in-class, highly potent, irreversible small-molecule inhibitor of the menin-MLL interaction is presented. M-525 targets cellular menin protein at sub-nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLL-regulated gene expression in MLL leukemia cells. M-525 demonstrates high cellular specificity over non-MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and co-crystal structure of M-525 in complex with menin firmly establish its mode of action. A single administration of M-525 effectively suppresses MLL-regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize M-525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.
['Xu|Shilin|S|', 'Aguilar|Angelo|A|', 'Xu|Tianfeng|T|', 'Zheng|Ke|K|', 'Huang|Liyue|L|', 'Stuckey|Jeanne|J|', 'Chinnaswamy|Krishnapriya|K|', 'Bernard|Denzil|D|', 'Fernández-Salas|Ester|E|', 'Liu|Liu|L|', 'Wang|Mi|M|', 'McEachern|Donna|D|', 'Przybranowski|Sally|S|', 'Foster|Caroline|C|', 'Wang|Shaomeng|S|0000-0002-8782-6950']
D000970:Antineoplastic Agents D001665:Binding Sites D045744:Cell Line, Tumor D049109:Cell Proliferation D018360:Crystallography, X-Ray D015195:Drug Design D011495:Histone-Lysine N-Methyltransferase D006801:Humans D056004:Molecular Dynamics Simulation D051788:Myeloid-Lymphoid Leukemia Protein D054730:Protein Interaction Domains and Motifs D017434:Protein Structure, Tertiary D011518:Proto-Oncogene Proteins D054852:Small Molecule Libraries D013329:Structure-Activity Relationship
irreversible inhibitors menin-MLL protein-protein interaction MLL leukemia drug design