The protein-protein interaction between menin and Mixed Lineage Leukemia 1 (MLL1) plays a critical role in a subset of aggressive acute leukemia, which are found in both adult and pediatric leukemia patients. We discovered and developed small molecule inhibitors of the menin-MLL1 interaction with sub-nanomolar activity in vitro, which demonstrate pronounced anti-leukemic effect in in vitro and in vivo models of acute leukemia with MLL1 translocations or NPM1 mutations. When applied as single agents, out best menin-MLL1 inhibitors induces complete remission or regression of leukemia in mouse models of leukemia, including patient-derived xenograft (PDX) models. Furthermore, combination of our menin inhibitors with kinase inhibitors (including FLT3 or CDK6 inhibitors) demonstrates even more pronounced effects in vivo in AML models with MLL1 translocations or NPM1 mutations, including long-lasting complete remission. Clinical studies are undergoing to explore the effectiveness of one of these compounds in leukemia patients. Overall, development of menin-MLL1 inhibitors represents one of only few examples of highly potent inhibitors targeting protein-protein interactions with a substantial promise as a new anti-cancer therapy, including pediatric leukemia patients.

Development of menin-MLL1 inhibitors as a treatment for acute leukemia

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.