Design of the First‐in‐Class, Highly Potent Irreversible Inhibitor Targeting the Menin‐MLL Protein–Protein Interaction. Issue 6 (15th January 2018)

• Record Type: Journal Article
• Authors: Xu, Shilin; Aguilar, Angelo; Xu, Tianfeng; Zheng, Ke; Huang, Liyue; Stuckey, Jeanne; Chinnaswamy, Krishnapriya; Bernard, Denzil; Fernández‐Salas, Ester; Liu, Liu; Wang, Mi; McEachern, Donna; Przybranowski, Sally; Foster, Caroline; Wang, Shaomeng
• Is Part Of: Angewandte Chemie international edition. Volume 57:Issue 6(2018)
• Page Start: 1601
• Page End: 1605
• Publication Date: 2018-01-15
• Subjects: drug design -- irreversible inhibitors -- menin-MLL protein–protein interaction -- MLL leukemia; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201711828
• Languages: English
• ISSNs: 1433-7851

Abstract

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. Abstract : Irreversible inhibitor M‐525 targets the menin‐MLL interaction. It is demonstrated that irreversible inhibition of menin is a promising therapeutic strategy for the treatment of MLL leukemia and may have advantages over reversible inhibitors.