orally active covalent menin-MLL PPI inhibitor
efficacy in xenograft (300 mpk PO QD)
warhead addition to rev. inh. and opt.
Journal of Medicinal Chemistry
University of Michigan, Ann Arbor, US
9. The University of Michigan menin-MLL inhibitor, M-1121, is a covalent protein-protein interaction inhibitor that is orally active and achieves complete tumor regression in a xenograft model (300 mpk PO QD). MLL gene fusions are drivers of leukemias via interaction with menin, and small molecule menin-MLL inhibitors have shown preliminary activity in trials (KO-539, NCT04067336 and SNDX-5613, NCT4065399). M-1121 has a non-covalent scaffold with features reminiscent of prior reversible inhibitors (e.g. MI-503 and VTP-50469) with an acrylamide warhead targeting MLL's Cys329. Though it is given at a high dose in mouse, the in vivo activity of the molecule is impressive given its large size, acrylamide warhead, the presence of two basic nitrogens, 7 rings, and several hydrogen-bond acceptor and donor…