title: Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo.
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.
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Dmitry
authors: D
authors: Borkin
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Shihan
authors: S
authors: He
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Hongzhi
authors: H
authors: Miao
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Katarzyna
authors: K
authors: Kempinska
authors: 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.
authors: Jonathan
authors: J
authors: Pollock
authors: 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.
authors: Jennifer
authors: J
authors: Chase
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Trupta
authors: T
authors: Purohit
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Bhavna
authors: B
authors: Malik
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Ting
authors: T
authors: Zhao
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Jingya
authors: J
authors: Wang
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Bo
authors: B
authors: Wen
authors: Department of Medicine, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors: Hongliang
authors: H
authors: Zong
authors: 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.
authors: Morgan
authors: M
authors: Jones
authors: Department of Medicine, Division of Hematology-Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Gwenn
authors: G
authors: Danet-Desnoyers
authors: Department of Medicine, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors: Monica L
authors: ML
authors: Guzman
authors: Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Moshe
authors: M
authors: Talpaz
authors: Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Dale L
authors: DL
authors: Bixby
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Duxin
authors: D
authors: Sun
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; School of Medicine, Indiana University, Indianapolis, IN 46202, USA.
authors: Jay L
authors: JL
authors: Hess
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Andrew G
authors: AG
authors: Muntean
authors: 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.
authors: Ivan
authors: I
authors: Maillard
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Tomasz
authors: T
authors: Cierpicki
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: jolantag@umich.edu.
authors: Jolanta
authors: J
authors: Grembecka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C497422:KMT2A protein, human; C105373:MEN1 protein, human; C484898:Men1 protein, mouse; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse