Browsing by Subject "Myeloid-Lymphoid Leukemia Protein"

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    Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo
    (Elsevier, 2015-04-13) 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 L.; Muntean, Andrew G.; Maillard, Ivan; Cierpicki, Tomasz; Grembecka, Jolanta; Dean, IU School of Medicine
    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.
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    Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia
    (Elsevier, 2014-01-23) Cao, Fang; Townsend, Elizabeth C.; Karatas, Hacer; Xu, Jing; Li, Li; Lee, Shirley; Liu, Liu; Chen, Yong; Ouillette, Peter; Zhu, Jidong; Hess, Jay L.; Atadja, Peter; Lei, Ming; Qin, Zhaohui; Malek, Sami; Wang, Shaomeng; Dou, Yali; IU School of Medicine
    Here we report a comprehensive characterization of our recently developed inhibitor MM-401 that targets the MLL1 H3K4 methyltransferase activity. MM-401 is able to specifically inhibit MLL1 activity by blocking MLL1-WDR5 interaction and thus the complex assembly. This targeting strategy does not affect other mixed-lineage leukemia (MLL) family histone methyltransferases (HMTs), revealing a unique regulatory feature for the MLL1 complex. Using MM-401 and its enantiomer control MM-NC-401, we show that inhibiting MLL1 methyltransferase activity specifically blocks proliferation of MLL cells by inducing cell-cycle arrest, apoptosis, and myeloid differentiation without general toxicity to normal bone marrow cells or non-MLL cells. More importantly, transcriptome analyses show that MM-401 induces changes in gene expression similar to those of MLL1 deletion, supporting a predominant role of MLL1 activity in regulating MLL1-dependent leukemia transcription program. We envision broad applications for MM-401 in basic and translational research.