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 Hess, Andrew G. Muntean & 3 others Ivan Maillard, Tomasz Cierpicki, Jolanta Grembecka

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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 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

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Leukemia
Genes
Genetic Translocation
Gene Fusion
Cell Survival
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Borkin, D., He, S., Miao, H., Kempinska, K., Pollock, J., Chase, J., ... 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

Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia invivo. / Borkin, Dmitry; He, Shihan; Miao, Hongzhi; Kempinska, Katarzyna; Pollock, Jonathan; Chase, Jennifer; Purohit, Trupta; Malik, Bhavna; Zhao, Ting; Wang, Jingya; Wen, Bo; Zong, Hongliang; Jones, Morgan; Danet-Desnoyers, Gwenn; Guzman, Monica L.; Talpaz, Moshe; Bixby, Dale L.; Sun, Duxin; Hess, Jay; Muntean, Andrew G.; Maillard, Ivan; Cierpicki, Tomasz; Grembecka, Jolanta.

In: Cancer Cell, Vol. 27, No. 4, 13.04.2015, p. 589-602.

Research output: Contribution to journalArticle

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, ML, Talpaz, M, Bixby, DL, Sun, D, Hess, J, Muntean, AG, Maillard, I, Cierpicki, T & Grembecka, J 2015, 'Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia invivo', Cancer Cell, vol. 27, no. 4, pp. 589-602. https://doi.org/10.1016/j.ccell.2015.02.016
Borkin, Dmitry ; He, Shihan ; Miao, Hongzhi ; Kempinska, Katarzyna ; Pollock, Jonathan ; Chase, Jennifer ; Purohit, Trupta ; Malik, Bhavna ; Zhao, Ting ; Wang, Jingya ; Wen, Bo ; Zong, Hongliang ; Jones, Morgan ; Danet-Desnoyers, Gwenn ; Guzman, Monica L. ; Talpaz, Moshe ; Bixby, Dale L. ; Sun, Duxin ; Hess, Jay ; Muntean, Andrew G. ; Maillard, Ivan ; Cierpicki, Tomasz ; Grembecka, Jolanta. / Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia invivo. In: Cancer Cell. 2015 ; Vol. 27, No. 4. pp. 589-602.
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AU - He, Shihan

AU - Miao, Hongzhi

AU - Kempinska, Katarzyna

AU - Pollock, Jonathan

AU - Chase, Jennifer

AU - Purohit, Trupta

AU - Malik, Bhavna

AU - Zhao, Ting

AU - Wang, Jingya

AU - Wen, Bo

AU - Zong, Hongliang

AU - Jones, Morgan

AU - Danet-Desnoyers, Gwenn

AU - Guzman, Monica L.

AU - Talpaz, Moshe

AU - Bixby, Dale L.

AU - Sun, Duxin

AU - Hess, Jay

AU - Muntean, Andrew G.

AU - Maillard, Ivan

AU - Cierpicki, Tomasz

AU - Grembecka, Jolanta

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