High-Affinity Small-Molecule Inhibitors of the Menin-Mixed Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein–Protein Interaction
Year: 2014
Type: article
Abstract: 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.
Source: Journal of Medicinal Chemistry
DOI: 10.1021/jm401868d
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Awards: G2202790698, The Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, G2896567508, G3231722022, G342476720, Translational Research in GI Cancer, G426311843, G4889817119, G5650519660, G7689402003, Screening for Inhibitors Targeting the Menin-MLL Interaction in MLL Related Leuke, G8091996919, Development of novel anti-leukemia agents targeting the menin-MLL interaction
OpenAlex ID: W2084754082