| Literature DB >> 25817203 |
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.
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.Entities:
Mesh：
Substances：
Year: 2015 PMID： 25817203 PMCID： PMC4415852 DOI： 10.1016/j.ccell.2015.02.016
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743