Abstract 2534: High-affinity small molecule inhibitors of the menin-MLL interaction reverse oncogenic transformation mediated by MLL fusion proteins in leukemia

Abstract

Abstract The protein-protein interaction (PPI) between menin and Mixed Lineage Leukemia (MLL) plays a critical role in acute leukemias with translocations of MLL gene, and inhibition of this interaction with small molecules represents a new potential therapeutic strategy for the MLL leukemia patients. We identified novel small molecule inhibitors of the menin-MLL interaction with distinct molecular scaffolds by performing a High Throughput Screening (HTS) of over 300,000 compounds. Extensive medicinal chemistry efforts performed for two lead classes to improve inhibitory activity of these compounds resulted in menin-MLL inhibitors with low nanomolar binding affinities. The menin-inhibitor co-crystal structures revealed that these compounds directly bind to menin and closely mimic the key interactions of MLL with menin, resulting in their high binding affinity. Interestingly, the hydroxymethylpiperidine class of the menin-MLL inhibitors extends beyond the MLL binding region on menin, providing additional opportunity for their optimization. We combined extensive crystallography studies with structure-based design to perform rational optimization and scaffold modification to rapidly improve activity and modulate physicochemical properties of the menin-MLL inhibitors. Treatment of MLL leukemia cells with the most potent menin-MLL inhibitors we developed resulted in very effective and selective inhibition of cell proliferation, induced apoptosis and differentiation of these cells. These effects were associated with downregulation of Hoxa9 and Meis1 expression, the downstream targets of MLL fusion proteins required for their leukemogenicity, demonstrating a very specific mechanism of action for these newly developed menin-MLL inhibitors. In vivo studies are currently undergoing to assess the effect of these compounds on leukemia progression in animal models of MLL leukemia. Our studies provide a novel and very attractive scaffolds for further development as a new potential therapeutic approach for the MLL leukemia patients. Citation Format: Jolanta E. Grembecka, Shihan He, Timothy J. Senter, Dmitry Borkin, Jonathan Pollock, Changho Han, Sunil Kumar Upadhyay, Trupta Purohit, Hongzhi Miao, Rocco D. Gogliotti D. Gogliotti, Craig W. Lindsley, Tomasz Cierpicki, Shaun R. Stauffer. High-affinity small molecule inhibitors of the menin-MLL interaction reverse oncogenic transformation mediated by MLL fusion proteins in leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2534. doi:10.1158/1538-7445.AM2014-2534