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

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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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Journal

Journal ID (iso-abbrev): Cancer Cell

Title: Cancer cell

ISSN (Electronic): 1878-3686

ISSN (Print): 1535-6108

Publication date (Electronic): Apr 13 2015

Volume: 27

Issue: 4

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.

Article

Publisher Item ID: S1535-6108(15)00066-5 Mid ID: NIHMS675650

DOI: 10.1016/j.ccell.2015.02.016

PMC ID: 4415852

PubMed ID: 25817203

SO-VID: 3ad2c220-57d9-475e-91b9-9a9e0d187378

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