High-Affinity Small-Molecule Inhibitors of the Menin-Mixed Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein-Protein Interaction

Journal Article · Thu Oct 02 00:00:00 EDT 2014 · J. Med. Chem.

DOI:https://doi.org/10.1021/jm401868d· OSTI ID:1129222

He, Shihan; Senter, Timothy J.; Pollock, Jonathan; Han, Changho; Upadhyay, Sunil Kumar; Purohit, Trupta; Gogliotti, Rocco D.; Lindsley, Craig W.; Cierpicki, Tomasz; Stauffer, Shaun R.; Grembecka, Jolanta ^[1]

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1. Michigan

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.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: OTHERUNIVERSITYNIH
• OSTI ID: 1129222
• Journal Information: J. Med. Chem., Vol. 57, Issue (4) ; 02, 2014
• Country of Publication: United States
• Language: ENGLISH