8E90

Inhibition of Human Menin by SNDX-5613

Summary for 8E90

• Entry DOI: 10.2210/pdb8e90/pdb
• Related: 7UJ4
• Descriptor: Isoform 2 of Menin, 2-({4-[7-({(1r,4r)-4-[(ethanesulfonyl)amino]cyclohexyl}methyl)-2,7-diazaspiro[3.5]nonan-2-yl]pyrimidin-5-yl}oxy)-N-ethyl-5-fluoro-N-(propan-2-yl)benzamide, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: human menin, transcription, m322i mutant inhibitor complex, sndx-5613
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 111377.57

Authors

McKeever, B.M.,KULKARNI, S.,McGeehan, G.M. (deposition date: 2022-08-26, release date: 2022-12-14, Last modification date: 2023-10-25)

Primary citation

Perner, F.,Stein, E.M.,Wenge, D.V.,Singh, S.,Kim, J.,Apazidis, A.,Rahnamoun, H.,Anand, D.,Marinaccio, C.,Hatton, C.,Wen, Y.,Stone, R.M.,Schaller, D.,Mowla, S.,Xiao, W.,Gamlen, H.A.,Stonestrom, A.J.,Persaud, S.,Ener, E.,Cutler, J.A.,Doench, J.G.,McGeehan, G.M.,Volkamer, A.,Chodera, J.D.,Nowak, R.P.,Fischer, E.S.,Levine, R.L.,Armstrong, S.A.,Cai, S.F.
MEN1 mutations mediate clinical resistance to menin inhibition.
Nature, 615:913-919, 2023

PubMed Abstract: Chromatin-binding proteins are critical regulators of cell state in haematopoiesis. Acute leukaemias driven by rearrangement of the mixed lineage leukaemia 1 gene (KMT2Ar) or mutation of the nucleophosmin gene (NPM1) require the chromatin adapter protein menin, encoded by the MEN1 gene, to sustain aberrant leukaemogenic gene expression programs. In a phase 1 first-in-human clinical trial, the menin inhibitor revumenib, which is designed to disrupt the menin-MLL1 interaction, induced clinical responses in patients with leukaemia with KMT2Ar or mutated NPM1 (ref. ). Here we identified somatic mutations in MEN1 at the revumenib-menin interface in patients with acquired resistance to menin inhibition. Consistent with the genetic data in patients, inhibitor-menin interface mutations represent a conserved mechanism of therapeutic resistance in xenograft models and in an unbiased base-editor screen. These mutants attenuate drug-target binding by generating structural perturbations that impact small-molecule binding but not the interaction with the natural ligand MLL1, and prevent inhibitor-induced eviction of menin and MLL1 from chromatin. To our knowledge, this study is the first to demonstrate that a chromatin-targeting therapeutic drug exerts sufficient selection pressure in patients to drive the evolution of escape mutants that lead to sustained chromatin occupancy, suggesting a common mechanism of therapeutic resistance.

PubMed: 36922589
DOI: 10.1038/s41586-023-05755-9

Experimental method

X-RAY DIFFRACTION (1.85 Å)