Targeting Menin in Acute Leukemia with Upregulated HOX Genes

摘要

Abstract The protein-protein interaction between menin and Mixed Lineage Leukemia 1 (MLL1) protein plays a critical role in acute leukemia with chromosomal translocations of the MLL1 gene, affecting both children and adults. Leukemia patients with MLL1 translocations have very poor prognosis, with only ~35% five-year survival rate, implying an urgent need for new therapies. The menin-MLL1 interaction also plays an important role in acute myeloid leukemia (AML) with mutations in the nucleophosmin 1 (NPM1) gene and with chromosomal translocations of the Nucleoporin 98 (NUP98) gene, both are associated with very poor prognosis in patients. The interaction of menin with MLL1 is required for the recruitment of MLL1 and MLL fusion proteins to the target genes (e.g. HOXA and MEIS1 genes), which are critical to leukemogenesis in the MLL1-rearranged, NPM1- mutated and NUP98-rearranged leukemias. Thus, the menin-MLL1 interaction plays a critical role in acute leukemia with upregulated HOX genes, constituting ~50% of all acute leukemia cases, supporting that small molecule inhibition of this interaction might provide new targeted therapy for leukemia patients. We pioneered development of small molecule inhibitors of the menin-MLL1 interaction, which directly bind to menin at the MLL1 binding site and strongly inhibit this protein-protein interaction. Subsequent medicinal chemistry optimization resulted in advanced menin-MLL1 inhibitors, such as MI-3454, with sub-nanomolar activity and high selectivity. MI-3454 demonstrates very pronounced activity in the MLL1-rearranged and NPM1-mutated leukemia models, blocking proliferation and inducing differentiation of leukemic cells through downregulation of HOX and MEIS1 genes, and strongly blocks leukemia progression in vivo in AML models, including complete remission. We have also developed and substantially optimized a new class of menin-MLL1 inhibitors that belong to a novel scaffold that fits very well to the MLL1 binding site on menin. These compounds have very pronounced activity in blocking the menin-MLL1 interaction and demonstrate strong effect in leukemia models, representing very attractive candidates to identify clinically relevant compounds with improved drug-like properties. In this project we propose to develop the next generation of menin inhibitors with picomolar activity derived from our advanced lead compounds for their clinical translation to AML patients. We will apply highly interdisciplinary approach, involving medicinal chemistry, structure-based design, pharmacokinetic (PK) studies and biological studies to develop highly optimized compounds with very strong in vivo efficacy in aggressive models of high HOXA leukemia, such as patient derived xenograft (PDX) models of AML, and with optimized drug-like properties. We will also study optimal combinations of our next generation of menin-MLL1 inhibitors with other agents to identify the best combinations for future clinical studies. We expect this work should result in the next generation of menin-MLL1 inhibitors with superior activity and drug-like properties over existing menin inhibitors that will be very attractive for clinical translation to leukemia patients