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

Dmitry Borkin; Shihan He; Hongzhi Miao; Katarzyna Kempinska; Jonathan Pollock; Jennifer Chase; Trupta Purohit; Bhavna Malik; Ting Zhao; Jingya Wang; Bo Wen; Hongliang Zong; Morgan Jones; Gwenn Danet-Desnoyers; Monica L Guzman; Moshe Talpaz; Dale L Bixby; Duxin Sun; Jay L Hess; Andrew G Muntean; Ivan Maillard; Tomasz Cierpicki; Jolanta Grembecka

doi:10.1016/j.ccell.2015.02.016

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. Epub 2015 Mar 26.

Authors

Dmitry Borkin¹, Shihan He¹, Hongzhi Miao¹, Katarzyna Kempinska¹, Jonathan Pollock², Jennifer Chase³, Trupta Purohit¹, Bhavna Malik¹, Ting Zhao⁴, Jingya Wang¹, Bo Wen⁴, Hongliang Zong⁵, Morgan Jones⁶, Gwenn Danet-Desnoyers⁷, Monica L Guzman⁵, Moshe Talpaz⁸, Dale L Bixby⁸, Duxin Sun⁴, Jay L Hess⁹, Andrew G Muntean¹, Ivan Maillard¹⁰, Tomasz Cierpicki¹, Jolanta Grembecka¹¹

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.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Disease Progression
Drug Evaluation, Preclinical
Female
Hematopoiesis / drug effects
Histone-Lysine N-Methyltransferase / genetics
Histone-Lysine N-Methyltransferase / metabolism
Humans
Mice
Mice, Inbred C57BL
Myeloid-Lymphoid Leukemia Protein / chemistry
Myeloid-Lymphoid Leukemia Protein / genetics
Myeloid-Lymphoid Leukemia Protein / metabolism*
Oncogene Proteins, Fusion / antagonists & inhibitors
Oncogene Proteins, Fusion / genetics
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism*
Tumor Cells, Cultured

Substances

Antineoplastic Agents
KMT2A protein, human
MEN1 protein, human
Men1 protein, mouse
Oncogene Proteins, Fusion
Proto-Oncogene Proteins
Myeloid-Lymphoid Leukemia Protein
Histone-Lysine N-Methyltransferase
Kmt2a protein, mouse

Associated data

GEO/GSE60673
PDB/4X5Y
PDB/4X5Z

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding