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.
Linking of fragments in neighboring binding sites is one of the optimization strategies in fragment-based drug discovery, where additive or even more substantial bioactivity improvements can be realized. However, such efforts present a considerable challenge when one fragment binds covalently to the target protein, as small modifications can influence the correct positioning of the covalent warhead toward the targeted nucleophilic residue. Here, we present a case study of fragment linking that yielded single-digit micromolar, covalent inhibitors of the SARS-CoV-2 main protease, starting from fragments that were inactive in the biochemical assay. Using structural information from a recent, high-throughput crystallographic fragment screen, we show that the success of fragment linking in the design of targeted covalent inhibitors is heavily impacted by several factors, including the warhead type, the labeling chemistry, and even subtle changes in the designed linker. Notably, we observe that induced fit effects might override the original fragment orientations in the linked molecule, highlighting the need for reliable structure verification, especially in consecutive rounds of fragment elaboration.
Levente Kollár, Levente M. Mihalovits, Dávid Bajusz, DamijanKnez, József Simon, Blake H. Balcomb, Daren Fearon, Stanislav Gobec, György M. K...
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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...
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Yoav Shamir, Nir London bioRxiv 2025.03.19.642201 doi: https://doi.org/10.1101/2025.03.19.642201 Recent years have seen an explosion in the...
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DOI Ansgar Oberheide, Maxime van den Oetelaar, Jakob Scheele, Jan Borggräfe, Semmy Engelen, Michael Sattler, Christian Ottmann, ...
