MI-503 and MI-463 demonstrate profound on-target activity in MLL leukemia cells
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MI-503 and MI-463 show substantial survival benefit in mouse models of MLL leukemia
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Menin-MLL inhibitors do not impair normal hematopoiesis in vivo
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MI-503 and MI-463 provide molecular scaffold for clinical lead identification
Summary
Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.