Abstract IA002: Targeted menin inhibition to disrupt leukemia fusion oncoproteins: from discovery to therapeutic applications

Abstract The protein-protein interaction between menin and Lysine Methyltransferase 2A (KMT2A; also known as Mixed Lineage Leukemia 1, MLL1) plays a critical role in various acute leukemia subtypes, including those driven by oncogenic fusion proteins such as KMT2A and NUP98 fusions. Our group pioneered the development of small-molecule inhibitors targeting the menin-KMT2A interaction, leading to ziftomenib (co-developed with Kura Oncology), which recently received FDA approval for AML treatment. Our efforts focused on the discovery and development of ziftomenib and its activity in fusion protein driven leukemias, both as a single agent and in combination therapies, will be discussed. Furthermore, we will also address ziftomenib’s activity against drug-induced menin mutations identified in AML patients that confer resistance. Finally, we will present our recent work on a new generation of menin inhibitors that block the most frequent drug-resistant menin mutans found in AML patients, providing a promising strategy to overcome resistance to current menin inhibitors. Citation Format: Jolanta Grembecka. Targeted menin inhibition to disrupt leukemia fusion oncoproteins: from discovery to therapeutic applications [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr IA002.