Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia invivo

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. MunteanIvan Maillard, Tomasz Cierpicki, Jolanta Grembecka

Research output: Contribution to journalArticle

137 Scopus citations

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 invivo and provide advanced molecular scaffold for clinical lead identification.

Original languageEnglish (US)
Pages (from-to)589-602
Number of pages14
JournalCancer Cell
Volume27
Issue number4
DOIs
StatePublished - Apr 13 2015

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Borkin, D., He, S., Miao, H., Kempinska, K., Pollock, J., Chase, J., Purohit, T., Malik, B., Zhao, T., Wang, J., Wen, B., Zong, H., Jones, M., Danet-Desnoyers, G., Guzman, M. L., Talpaz, M., Bixby, D. L., Sun, D., Hess, J. L., ... Grembecka, J. (2015). Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia invivo. Cancer Cell, 27(4), 589-602. https://doi.org/10.1016/j.ccell.2015.02.016