Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein-Protein Interaction
Angew. Chem. Int. Ed., 2018
DOI: 10.1002/anie.201711828
Shaomeng Wang, Shilin Xu, Angelo Aguilar, Tianfeng Xu, Ke Zheng, Liyue Huang, Jeanne Stuckey, Krishnapriya Chinnaswamy, Denzil Bernard, Ester Fernández-Salas, Liu Liu, Mi Wang, Donna McEachern, Sally Przybranowski, Caroline Foster
We report the structure-based design of M-525 as the first-in-class, highly potent, irreversible small-molecule inhibitor of the menin-MLL interaction. M-525 targets cellular menin protein at sub-nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in suppression of MLL-regulated gene expression in MLL leukemia cells. M-525 demonstrates high cellular specificity over non-MLL leukemia cells and is >30-times more potent than its corresponding reversible inhibitors. Mass spectroscopic 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. Our study demonstrates that irreversible inhibition of menin may represent a promising therapeutic strategy for MLL leukemia.
A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs. @CovalentMod on Twitter, @covalentmod@mstdn.science on Mastodon, and @covalentmod.bsky.social on BlueSky
Diethenyl Sulfoximine (DESI) as an Irreversible Lysine-Targeting Warhead Enables the Design of Covalent Allosteric EGFR Inhibitor
Huiqi Xu, Hongjin Zhang, Suyun Jia, Yanxin Tao, Quanpeng Wei, Yingao Wang, Xuechen Liu, Yuqing Zhang, Xinpeng Ning, Yuyan Shi, Can Jin, Ke D...
-
Design, synthesis and biological evaluation of the activity-based probes for FGFR covalent inhibitorDandan Zhu, Zijian Zheng, Huixin Huang, Xiaojuan Chen, Shuhong Zhang, Zhuchu Chen, Ting Liu, Guangyu Xu, Ying Fu, Yongheng Chen, European Jo...
-
DOI Ansgar Oberheide, Maxime van den Oetelaar, Jakob Scheele, Jan Borggräfe, Semmy Engelen, Michael Sattler, Christian Ottmann, ...
-
Özge Ünsal, Z. Selin Bacaksiz, Vladislav Khamraev, Vittorio Montanari, Martin Beinborn, and Krishna Kumar ACS Chemical Biology 2024 DOI: ...