Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia in vivo [electronic resource].
- Published
- Washington, D.C. : United States. Dept. of Energy. Office of Basic Energy Sciences, 2015.
Oak Ridge, Tenn. : Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy - Physical Description
- pages 589-602 : digital, PDF file
- Additional Creators
- United States. Department of Energy. Office of Basic Energy Sciences and United States. Department of Energy. Office of Scientific and Technical Information
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- Restrictions on Access
- Free-to-read Unrestricted online access
- Summary
- 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. In this paper, 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. In conclusion, 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.
- Report Numbers
- E 1.99:1344392
- Subject(s)
- Note
- Published through SciTech Connect.
03/26/2015.
": S1535610815000665"
Cancer Cell 27 4 ISSN 1535-6108 AM
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.
Univ. of Michigan, Ann Arbor, MI (United States) - Funding Information
- AC02-06CH11357
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