Structure-Based Discovery of M-89 as a Highly Potent Inhibitor of the Menin-Mixed Lineage Leukemia (Menin-MLL) Protein–Protein Interaction
Open accessAbstract
Inhibition of the menin-mixed lineage leukemia (MLL) protein–protein interaction is a promising new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein our structure-based design, synthesis, and evaluation of a new class of small-molecule inhibitors of the menin-MLL interaction (hereafter called menin inhibitors). Our efforts have resulted in the discovery of highly potent menin inhibitors, as exemplified by compound 42 (M-89). M-89 binds to menin with a K d value of 1.4 nM and effectively engages cellular menin protein at low nanomolar concentrations. M-89 inhibits cell growth in the MV4;11 and MOLM-13 leukemia cell lines carrying MLL fusion with IC 50 values of 25 and 55 nM, respectively, and demonstrates >100-fold selectivity over the HL-60 leukemia cell line lacking MLL fusion. The determination of a co-crystal structure of M-89 in a complex with menin provides the structural basis for their high-affinity interaction. Further optimization of M-89 may lead to a new class of therapy for the treatment of MLL leukemia.
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Developing small molecule inhibitors to directly disrupt the MLL-menin interaction is a potential strategy for leukemia treatment.
“Therefore, developing small molecule inhibitors to directly disrupt the MLL-menin interaction is a potential strategy for leukemia treatment [100, 101].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [100]
In leukemia, the MLL protein interacts with menin to promote oncogenic activity.
“For example, in leukemia, the mixed lineage leukemia (MLL) protein interacts with menin to promote oncogenic activity.”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [100]
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- Authors
- Aguilar, A., Zheng, K., Xu, T., Xu, S., Huang, L., Fernandez-Salas, E., Liu, L., Bernard, D., Harvey, K. P., Foster, C., McEachern, D., Stuckey, J., Chinnaswamy, K., Delproposto, J., Kampf, J. W., & Wang, S.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Wang, Shaomeng
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-06-22
- Volume
- 62
- Issue
- 13
- Pages
- 6015-6034
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC7057177
- OpenAlex
- W2951484711
- Cited by
- 39
- References
- 34
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 11 · 2023: 1 · 2022: 4 · 2021: 8 · 2020: 3 · 2019: 3
- FWCI
- 3.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- National Cancer Institute (P30CA046592, R01CA208267)
- Prostate Cancer Foundation
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- menin inhibitors, MLL fusion, MLL leukemia, acute leukemia, structure-based drug design, small molecule inhibitors, co-crystal structure, MV4-11 cells, MOLM-13 cells, cell growth inhibition
- MeSH terms
- Acute Disease, Humans, Leukemia, Myeloid, Models, Chemical, Protein Binding, Proto-Oncogene Proteins, Structure-Activity Relationship, Molecular Structure, Crystallography, X-Ray, HL-60 Cells, Cell Line, Tumor, Cell Proliferation, Myeloid-Lymphoid Leukemia Protein, Small Molecule Libraries, Drug Discovery
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