High-Affinity Small-Molecule Inhibitors of the Menin-Mixed Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein–Protein Interaction
Open accessAbstract
The protein–protein interaction (PPI) between menin and mixed lineage leukemia (MLL) plays a critical role in acute leukemias, and inhibition of this interaction represents a new potential therapeutic strategy for MLL leukemias. We report development of a novel class of small-molecule inhibitors of the menin–MLL interaction, the hydroxy- and aminomethylpiperidine compounds, which originated from HTS of ∼288000 small molecules. We determined menin–inhibitor co-crystal structures and found that these compounds closely mimic all key interactions of MLL with menin. Extensive crystallography studies combined with structure-based design were applied for optimization of these compounds, resulting in MIV-6R, which inhibits the menin–MLL interaction with IC50 = 56 nM. Treatment with MIV-6 demonstrated strong and selective effects in MLL leukemia cells, validating specific mechanism of action. Our studies provide novel and attractive scaffold as a new potential therapeutic approach for MLL leukemias and demonstrate an example of PPI amenable to inhibition by small molecules.
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There are three different classes of PPI: short continuous peptide epitopes, secondary structural epitopes, and tertiary structural epitopes.
“Generally, there are three different classes of PPI: short continuous peptide epitopes, secondary structural epitopes, and tertiary structural epitopes.”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [29]
Compared with primary and secondary structure of epitopes, the interfaces of tertiary epitopes are more dynamic and prevalent.
“Compared with primary and secondary structure of epitopes, the interfaces of tertiary epitopes are more dynamic and prevalent (Fig. 2c) [29].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [29]
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- Authors
- He, S., Senter, T. J., Pollock, J., Han, C., Upadhyay, S. K., Purohit, T., Gogliotti, R. D., Lindsley, C. W., Cierpicki, T., Stauffer, S. R., & Grembecka, J.
- Affiliations
- University of Michigan (US)
- Vanderbilt University (US)
- Corresponding author
- Grembecka, Jolanta
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2014-01-28
- Volume
- 57
- Issue
- 4
- Pages
- 1543-1556
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC3983337
- OpenAlex
- W2084754082
- Cited by
- 99
- References
- 40
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 11 · 2023: 3 · 2022: 3 · 2021: 9 · 2020: 9 · 2019: 14 · 2018: 8 · 2017: 10 · 2016: 8 · 2015: 7 · 2014: 6
- FWCI
- 4.51
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Medicinal Chemistry (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- American Cancer Society (RSG-11-082-01-DMC, RSG-13-130-01-CDD)
- NIH Office of the Director (1R01CA160467, 1R03MH084875, 1U54 MH084659)
- Michigan Economic Development Corporation (085P1000817)
- Leukemia and Lymphoma Society (LLS Scholar 1215-14, LLS TRP 6116-12)
- Office of Basic Energy Sciences (DE-AC02-06CH11357)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- protein-protein interaction inhibitors, small molecule inhibitors, MLL, acute leukemia, co-crystal structure, structure-based drug design, high-affinity inhibitors
- MeSH terms
- Calorimetry, Humans, Magnetic Resonance Spectroscopy, Piperidines, Protein Binding, Crystallography, X-Ray, Spectrometry, Mass, Electrospray Ionization, Myeloid-Lymphoid Leukemia Protein, Small Molecule Libraries, HEK293 Cells, Hydrophobic and Hydrophilic Interactions
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