Progress towards small molecule inhibitors of the Menin-Mixed Lineage Leukemia (MLL) interaction with in vivo utility

A series of optimized Menin-Mixed Lineage Leukemia (MLL) protein-protein interaction inhibitors are reported leading to second generation probe ML399. HTS the Molecular Libraries Probe Production Centers Network (MLPCN) screening led to several chemotypes, including a piperidine class which successfully led to first generation probe ML227. Metabolic instability, potency, and ancillary pharmacology activity of ML227 were identified as limiting features. In order to enhance the utility of a menin-MLL inhibitor probe for in vivo proof-of-mechanism studies, a medicinal chemistry effort was reinitiated with a structure-based design approach incorporated. Novel menin-MLL inhibitors with improved potency and DMPK properties were identified leading to declared probe ML399. SAR and characterization of compounds within the series is described.