6O5I

Menin in complex with MI-3454

Summary for 6O5I

• Entry DOI: 10.2210/pdb6o5i/pdb
• Descriptor: Menin, ~{N}-[3-[[2-cyano-4-methyl-5-[[4-[[2-(methylamino)-6-[2,2,2-tris(fluoranyl)ethyl]thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indol-1-yl]methyl]-1-bicyclo[1.1.1]pentanyl]methanamide, DIMETHYL SULFOXIDE, ... (6 entities in total)
• Functional Keywords: menin-inhibitor complex, protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 56031.93

Authors

Linhares, B.M.,Klossowski, S.,Cierpicki, T.,Grembecka, J. (deposition date: 2019-03-03, release date: 2020-01-08, Last modification date: 2023-10-11)

Primary citation

Klossowski, S.,Miao, H.,Kempinska, K.,Wu, T.,Purohit, T.,Kim, E.,Linhares, B.M.,Chen, D.,Jih, G.,Perkey, E.,Huang, H.,He, M.,Wen, B.,Wang, Y.,Yu, K.,Lee, S.C.,Danet-Desnoyers, G.,Trotman, W.,Kandarpa, M.,Cotton, A.,Abdel-Wahab, O.,Lei, H.,Dou, Y.,Guzman, M.,Peterson, L.,Gruber, T.,Choi, S.,Sun, D.,Ren, P.,Li, L.S.,Liu, Y.,Burrows, F.,Maillard, I.,Cierpicki, T.,Grembecka, J.
Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia.
J.Clin.Invest., 130:981-997, 2020

PubMed Abstract: The protein-protein interaction between menin and mixed lineage leukemia 1 (MLL1) plays a critical role in acute leukemias with translocations of the MLL1 gene or with mutations in the nucleophosmin 1 (NPM1) gene. As a step toward clinical translation of menin-MLL1 inhibitors, we report development of MI-3454, a highly potent and orally bioavailable inhibitor of the menin-MLL1 interaction. MI-3454 profoundly inhibited proliferation and induced differentiation in acute leukemia cells and primary patient samples with MLL1 translocations or NPM1 mutations. When applied as a single agent, MI-3454 induced complete remission or regression of leukemia in mouse models of MLL1-rearranged or NPM1-mutated leukemia, including patient-derived xenograft models, through downregulation of key genes involved in leukemogenesis. We also identified MEIS1 as a potential pharmacodynamic biomarker of treatment response with MI-3454 in leukemia, and demonstrated that this compound is well tolerated and did not impair normal hematopoiesis in mice. Overall, this study demonstrates, for the first time to our knowledge, profound activity of the menin-MLL1 inhibitor as a single agent in clinically relevant PDX models of leukemia. These data provide a strong rationale for clinical translation of MI-3454 or its analogs for leukemia patients with MLL1 rearrangements or NPM1 mutations.

PubMed: 31855575
DOI: 10.1172/JCI129126

Experimental method

X-RAY DIFFRACTION (1.24025624626 Å)