2. Academic Validation
  3. Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia

Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia

  • J Clin Invest. 2020 Feb 3;130(2):981-997. doi: 10.1172/JCI129126.
Szymon Klossowski 1,  Hongzhi Miao 1,  Katarzyna Kempinska 1,  Tao Wu 2,  Trupta Purohit 1,  EunGi Kim 1,  Brian M Linhares 1,  Dong Chen 1,  Gloria Jih 3,  Eric Perkey 3,  Huang Huang 1,  Miao He 4,  Bo Wen 4,  Yi Wang 2,  Ke Yu 2,  Stanley Chun-Wei Lee 5,  Gwenn Danet-Desnoyers 6,  Winifred Trotman 6,  Malathi Kandarpa 7,  Anitria Cotton 8,  Omar Abdel-Wahab 5,  Hongwei Lei 1,  Yali Dou 1,  Monica Guzman 9,  Luke Peterson 7,  Tanja Gruber 8,  Sarah Choi 1,  Duxin Sun 4,  Pingda Ren 2 10,  Lian-Sheng Li 2,  Yi Liu 2,  Francis Burrows 10,  Ivan Maillard 3 6,  Tomasz Cierpicki 1,  Jolanta Grembecka 1
Affiliations

Affiliations

  • 1 Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • 2 Wellspring Biosciences, Inc., San Diego, California, USA.
  • 3 Life Sciences Institute and.
  • 4 College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
  • 5 Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 6 Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • 7 Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
  • 8 Saint Jude Children's Hospital, Memphis, Tennessee, USA.
  • 9 Weill Cornell Medicine, New York, New York, USA.
  • 10 Kura Oncology, Inc., San Diego, California, USA.
PMID: 31855575 DOI: 10.1172/JCI129126
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.

Keywords

Drug therapy; Hematology; Leukemias; Therapeutics.

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