Overcoming resistance to menin patient mutations in leukemia

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

Abstract The protein-protein interaction involving menin and MLL1 (Mixed Lineage Leukemia 1, also known as KMT2A) plays a critical role in acute leukemias with upregulated HOX genes, including leukemias with translocations of the MLL1 gene, mutations in nucleophosmin (NPM1) gene or NUP98 rearrangements. Patients with these leukemia sub-types have very poor prognosis (~35% five-year survival), emphasizing the need for new therapies. Our group has developed the first-in-class menin-MLL1 inhibitors, which directly bind to menin at the MLL1 binding site and strongly inhibit this protein-protein interaction, abrogating leukemia progression in advanced pre-clinical models of high HOX Acute Myeloid Leukemia (AML). Our pioneering efforts in this field led to clinical translation of menin inhibitors that are currently under clinical evaluation in AML patients. However, clinical studies with the menin inhibitor Revumenib revealed somatic mutations M327I/V, T349M, G331D/R (which we called the MTG mutations) in the MEN1 gene (encoding menin) in ~39% of AML patients, leading to clinical resistance. These acquired mutations occur in the inhibitor binding site, resulting in reduced drug binding to menin and leukemia relapse. Since all menin inhibitors in clinical evaluation bind to the same binding site where the mutations occur, they are not effective against the menin patient mutants. Thus, a new generation of menin inhibitors is required to overcome resistance and provide an effective treatment for AML patients. In this project, we propose to develop the next generation of menin inhibitors with high potency (sub-nanomolar) against both menin WT and menin patient mutants to overcome resistance observed for the current menin inhibitors. To accomplish this goal, we developed a new class of very potent menin inhibitors with similar activity against menin WT and the most frequent menin mutants found in patients. These compounds demonstrate strong activity in leukemia cells and mouse xenograft leukemia models harboring the MTG patient mutations in menin. Here, we will apply highly interdisciplinary approach involving medicinal chemistry, structure-based design, pharmacokinetic (PK) studies and biological studies to develop highly optimized compounds effectively blocking menin WT and all (or at least majority) of menin patient mutants. Then, we will assess the efficacy of these compounds in xenografts and PDX models of high HOX leukemia with menin WT and mutants. We expect this study will result in the next generation of menin inhibitors that will overcome resistance resulting from menin patient mutations preventing leukemia relapse.