Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity

David S. Rogawski, Jing Deng, Hao Li, Hongzhi Miao, Dmitry Borkin, Trupta Purohit, Jiho Song, Jennifer Chase, Shuangjiang Li, Juliano Ndoj, Szymon Klossowski, EunGi Kim, Fengbiao Mao, Bo Zhou, James Ropa, Marta Z. Krotoska, Zhuang Jin, Patricia Ernst, Xiaomin Feng, Gang Huang, Kenichi Nishioka, Samantha Kelly, Miao He, Bo Wen, Duxin Sun, Andrew Muntean, Yali Dou, Ivan Maillard, Tomasz Cierpicki () and Jolanta Grembecka ()
Additional contact information
David S. Rogawski: University of Michigan
Jing Deng: University of Michigan
Hao Li: University of Michigan
Hongzhi Miao: University of Michigan
Dmitry Borkin: University of Michigan
Trupta Purohit: University of Michigan
Jiho Song: University of Michigan
Jennifer Chase: University of Michigan
Shuangjiang Li: University of Michigan
Juliano Ndoj: University of Michigan
Szymon Klossowski: University of Michigan
EunGi Kim: University of Michigan
Fengbiao Mao: University of Michigan
Bo Zhou: University of Michigan
James Ropa: University of Michigan
Marta Z. Krotoska: University of Michigan
Zhuang Jin: University of Michigan
Patricia Ernst: University of Colorado Denver, Anschutz Medical Campus
Xiaomin Feng: Cincinnati Children’s Hospital
Gang Huang: Cincinnati Children’s Hospital
Kenichi Nishioka: Enoki 1-1-5, Musashimurayama
Samantha Kelly: University of Pennsylvania
Miao He: University of Michigan
Bo Wen: University of Michigan
Duxin Sun: University of Michigan
Andrew Muntean: University of Michigan
Yali Dou: University of Michigan
Ivan Maillard: University of Michigan
Tomasz Cierpicki: University of Michigan
Jolanta Grembecka: University of Michigan

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-23152-6

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