molecules of the month


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

1 min read

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…

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