Complexity of Blocking Bivalent Protein–Protein Interactions: Development of a Highly Potent Inhibitor of the Menin–Mixed-Lineage Leukemia Interaction
Abstract
The protein–protein interaction between menin and mixed-lineage leukemia 1 (MLL1) plays an important role in development of acute leukemia with translocations of the MLL1 gene and in solid tumors. Here, we report the development of a new generation of menin–MLL1 inhibitors identified by structure-based optimization of the thienopyrimidine class of compounds. This work resulted in compound 28 (MI-1481), which showed very potent inhibition of the menin–MLL1 interaction (IC50 = 3.6 nM), representing the most potent reversible menin–MLL1 inhibitor reported to date. The crystal structure of the menin-28 complex revealed a hydrogen bond with Glu366 and hydrophobic interactions, which contributed to strong inhibitory activity of 28. Compound 28 also demonstrates pronounced activity in MLL leukemia cells and in vivo in MLL leukemia models. Thus, we report 28 is a valuable menin–MLL1 inhibitor that can be used for potential therapeutic applications and in further studies regarding the role of menin in cancer.
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- National Institutes of Health (NIH); Leukemia and Lymphoma Society LLS Scholar; American Cancer Society (ACS); USDOE Office of Science (SC), Basic Energy Sciences (BES); Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor
- OSTI Identifier:
- 1544860
- Grant/Contract Number:
- R01 (1R01CA160467); R01 (1R01CA200660); R01 (1R01CA201204); 1215-14; RSG-13-130-01-CDD; AC02-06CH11357; 085P1000817
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Medicinal Chemistry
- Additional Journal Information:
- Journal Volume: 61; Journal Issue: 11; Journal ID: ISSN 0022-2623
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 60 APPLIED LIFE SCIENCES; Indoles; Assays; Rodent models; Inhibitors; Inhibition
Citation Formats
Borkin, Dmitry, Klossowski, Szymon, Pollock, Jonathan, Miao, Hongzhi, Linhares, Brian M., Kempinska, Katarzyna, Jin, Zhuang, Purohit, Trupta, Wen, Bo, He, Miao, Sun, Duxin, Cierpicki, Tomasz, and Grembecka, Jolanta. Complexity of Blocking Bivalent Protein–Protein Interactions: Development of a Highly Potent Inhibitor of the Menin–Mixed-Lineage Leukemia Interaction. United States: N. p., 2018.
Web. doi:10.1021/acs.jmedchem.8b00071.
Borkin, Dmitry, Klossowski, Szymon, Pollock, Jonathan, Miao, Hongzhi, Linhares, Brian M., Kempinska, Katarzyna, Jin, Zhuang, Purohit, Trupta, Wen, Bo, He, Miao, Sun, Duxin, Cierpicki, Tomasz, & Grembecka, Jolanta. Complexity of Blocking Bivalent Protein–Protein Interactions: Development of a Highly Potent Inhibitor of the Menin–Mixed-Lineage Leukemia Interaction. United States. https://doi.org/10.1021/acs.jmedchem.8b00071
Borkin, Dmitry, Klossowski, Szymon, Pollock, Jonathan, Miao, Hongzhi, Linhares, Brian M., Kempinska, Katarzyna, Jin, Zhuang, Purohit, Trupta, Wen, Bo, He, Miao, Sun, Duxin, Cierpicki, Tomasz, and Grembecka, Jolanta. Tue .
"Complexity of Blocking Bivalent Protein–Protein Interactions: Development of a Highly Potent Inhibitor of the Menin–Mixed-Lineage Leukemia Interaction". United States. https://doi.org/10.1021/acs.jmedchem.8b00071. https://www.osti.gov/servlets/purl/1544860.
@article{osti_1544860,
title = {Complexity of Blocking Bivalent Protein–Protein Interactions: Development of a Highly Potent Inhibitor of the Menin–Mixed-Lineage Leukemia Interaction},
author = {Borkin, Dmitry and Klossowski, Szymon and Pollock, Jonathan and Miao, Hongzhi and Linhares, Brian M. and Kempinska, Katarzyna and Jin, Zhuang and Purohit, Trupta and Wen, Bo and He, Miao and Sun, Duxin and Cierpicki, Tomasz and Grembecka, Jolanta},
abstractNote = {The protein–protein interaction between menin and mixed-lineage leukemia 1 (MLL1) plays an important role in development of acute leukemia with translocations of the MLL1 gene and in solid tumors. Here, we report the development of a new generation of menin–MLL1 inhibitors identified by structure-based optimization of the thienopyrimidine class of compounds. This work resulted in compound 28 (MI-1481), which showed very potent inhibition of the menin–MLL1 interaction (IC50 = 3.6 nM), representing the most potent reversible menin–MLL1 inhibitor reported to date. The crystal structure of the menin-28 complex revealed a hydrogen bond with Glu366 and hydrophobic interactions, which contributed to strong inhibitory activity of 28. Compound 28 also demonstrates pronounced activity in MLL leukemia cells and in vivo in MLL leukemia models. Thus, we report 28 is a valuable menin–MLL1 inhibitor that can be used for potential therapeutic applications and in further studies regarding the role of menin in cancer.},
doi = {10.1021/acs.jmedchem.8b00071},
journal = {Journal of Medicinal Chemistry},
number = 11,
volume = 61,
place = {United States},
year = {Tue May 08 00:00:00 EDT 2018},
month = {Tue May 08 00:00:00 EDT 2018}
}
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