6B41

Menin bound to M-525

Summary for 6B41

• Entry DOI: 10.2210/pdb6b41/pdb
• Descriptor: Menin, methyl {(1S,2R)-2-[(S)-cyano[1-({1-[4-({1-[4-(dimethylamino)butanoyl]azetidin-3-yl}sulfonyl)phenyl]azetidin-3-yl}methyl)piperidin-4-yl](3-fluorophenyl)methyl]cyclopentyl}carbamate, praseodymium triacetate, ... (4 entities in total)
• Functional Keywords: covalent inhibitor, men1 syndrome, leukemia, protein binding-inhibitor complex, protein binding/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : O00255
• Total number of polymer chains: 1
• Total formula weight: 63070.33

Authors

Stuckey, J.A. (deposition date: 2017-09-25, release date: 2018-01-24, Last modification date: 2024-10-23)

Primary citation

Xu, S.,Aguilar, A.,Xu, T.,Zheng, K.,Huang, L.,Stuckey, J.,Chinnaswamy, K.,Bernard, D.,Fernandez-Salas, E.,Liu, L.,Wang, M.,McEachern, D.,Przybranowski, S.,Foster, C.,Wang, S.
Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein-Protein Interaction.
Angew. Chem. Int. Ed. Engl., 57:1601-1605, 2018

PubMed Abstract: 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.

PubMed: 29284071
DOI: 10.1002/anie.201711828

Experimental method

X-RAY DIFFRACTION (2.61 Å)