Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein–Protein Interaction
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.
- Authors:
-
- Univ. of Michigan, Ann Arbor, MI (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1438913
- Alternate Identifier(s):
- OSTI ID: 1416992
- Grant/Contract Number:
- AC02-06CH11357
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Angewandte Chemie (International Edition)
- Additional Journal Information:
- Journal Name: Angewandte Chemie (International Edition); Journal Volume: 57; Journal Issue: 6; Journal ID: ISSN 1433-7851
- Publisher:
- Wiley
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; rug design; irreversible inhibitors; menin-MLL; protein-protein interaction; MLL leukemia
Citation Formats
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, and Wang, Shaomeng. Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein–Protein Interaction. United States: N. p., 2017.
Web. doi:10.1002/anie.201711828.
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. Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein–Protein Interaction. United States. https://doi.org/10.1002/anie.201711828
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, and Wang, Shaomeng. Thu .
"Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein–Protein Interaction". United States. https://doi.org/10.1002/anie.201711828. https://www.osti.gov/servlets/purl/1438913.
@article{osti_1438913,
title = {Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein–Protein Interaction},
author = {Xu, Shilin and Aguilar, Angelo and Xu, Tianfeng and Zheng, Ke and Huang, Liyue and Stuckey, Jeanne and Chinnaswamy, Krishnapriya and Bernard, Denzil and Fernández‐Salas, Ester and Liu, Liu and Wang, Mi and McEachern, Donna and Przybranowski, Sally and Foster, Caroline and Wang, Shaomeng},
abstractNote = {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.},
doi = {10.1002/anie.201711828},
journal = {Angewandte Chemie (International Edition)},
number = 6,
volume = 57,
place = {United States},
year = {Thu Dec 28 00:00:00 EST 2017},
month = {Thu Dec 28 00:00:00 EST 2017}
}
Web of Science
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