2. Academic Validation
  3. Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo

Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo

  • Cancer Cell. 2015 Apr 13;27(4):589-602. doi: 10.1016/j.ccell.2015.02.016.
Dmitry Borkin 1,  Shihan He 1,  Hongzhi Miao 1,  Katarzyna Kempinska 1,  Jonathan Pollock 2,  Jennifer Chase 3,  Trupta Purohit 1,  Bhavna Malik 1,  Ting Zhao 4,  Jingya Wang 1,  Bo Wen 4,  Hongliang Zong 5,  Morgan Jones 6,  Gwenn Danet-Desnoyers 7,  Monica L Guzman 5,  Moshe Talpaz 8,  Dale L Bixby 8,  Duxin Sun 4,  Jay L Hess 9,  Andrew G Muntean 1,  Ivan Maillard 10,  Tomasz Cierpicki 1,  Jolanta Grembecka 11
Affiliations

Affiliations

  • 1 Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 2 Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Graduate Program in Molecular and Cellular Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 3 Center for Stem Cell Biology, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 4 Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
  • 5 Department of Medicine, Weill Medical College of Cornell University, New York, NY 10065, USA.
  • 6 Center for Stem Cell Biology, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI 48109, USA.
  • 7 Department of Medicine, Division of Hematology-Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 8 Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • 9 Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; School of Medicine, Indiana University, Indianapolis, IN 46202, USA.
  • 10 Center for Stem Cell Biology, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 11 Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: jolantag@umich.edu.
PMID: 25817203 DOI: 10.1016/j.ccell.2015.02.016
Abstract

Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.

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