The development of a novel small molecule protein-protein interaction (PPI) inhibitor as a potential theurapeutic approach for the treatement of mixed lineage leukemia (MLL) will be discussed. The protein-protein interaction between menin and MLL is critical for oncogenic activity of MLL fusion proteins, resulting from translocations of the MLL gene. Patients with MLL-associated leukemias have very poor prognoses, with an estimated 35% overall five-year survival rate. Inhibition of this interaction with small molecule PPI inhibitors represents a novel therapeutic target.Optimization of a hydroxymethyl piperidine series identified from a high-throughput screen of ~288,000 compounds through the NIH Molecular Libraries Program identified initial probe ML227, which closely mimics many key interactions of MLL with menin. Extensive crystallography studies enabled a structure-guided design approach for the optimization of this series. Each region was systematically studied to engage in favorable interactions with menin that were not observed in the HTS hit while addressing metabolic and pharmacokinetic liabilites. This resulted in the second generation probe ML399.Improvements in potency and physicochemical properties to ML227 will allow for evaluation in animal models of mixed lineage leukemia and provides an example of PPI inhibition in the context of epigenetic regulation.

Structure-guided design of inhibitors of the menin-mixed lineage leukemia (MLL) interaction for the treatment of MLL-associated leukemias

248th National Meeting (2014)

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