Browsing by Author "Chase, Jennifer"

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    Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity
    (Springer Nature, 2021-05-14) Rogawski, David S.; Deng, Jing; Li, Hao; Miao, Hongzhi; Borkin, Dmitry; Purohit, Trupta; Song, Jiho; Chase, Jennifer; Li, Shuangjiang; Ndoj, Juliano; Klossowski, Szymon; Kim, EunGi; Mao, Fengbiao; Zhou, Bo; Ropa, James; Krotoska, Marta Z.; Jin, Zhuang; Ernst, Patricia; Feng, Xiaomin; Huang, Gang; Nishioka, Kenichi; Kelly, Samantha; He, Miao; Wen, Bo; Sun, Duxin; Muntean, Andrew; Dou, Yali; Maillard, Ivan; Cierpicki, Tomasz; Grembecka, Jolanta; Microbiology and Immunology, School of Medicine
    ASH1L histone methyltransferase plays a crucial role in the pathogenesis of different diseases, including acute leukemia. While ASH1L represents an attractive drug target, developing ASH1L inhibitors is challenging, as the catalytic SET domain adapts an inactive conformation with autoinhibitory loop blocking the access to the active site. Here, by applying fragment-based screening followed by medicinal chemistry and a structure-based design, we developed first-in-class small molecule inhibitors of the ASH1L SET domain. The crystal structures of ASH1L-inhibitor complexes reveal compound binding to the autoinhibitory loop region in the SET domain. When tested in MLL leukemia models, our lead compound, AS-99, blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo. This work validates the ASH1L SET domain as a druggable target and provides a chemical probe to further study the biological functions of ASH1L as well as to develop therapeutic agents.
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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.