APA
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Rogawski, D., Deng, J., Li, H., Miao, H., Borkin, D., Purohit, T., … Grembecka, J. (2021). Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity. Nature Communications.
Chicago/Turabian
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Rogawski, D., Jing Deng, Hao Li, H. Miao, D. Borkin, Trupta Purohit, Jiho Song, et al. “Discovery of First-in-Class Inhibitors of ASH1L Histone Methyltransferase with Anti-Leukemic Activity.” Nature Communications (2021).
MLA
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Rogawski, D., et al. “Discovery of First-in-Class Inhibitors of ASH1L Histone Methyltransferase with Anti-Leukemic Activity.” Nature Communications, 2021.
BibTeX Click to copy
@article{d2021a,
title = {Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity},
year = {2021},
journal = {Nature Communications},
author = {Rogawski, D. and Deng, Jing and Li, Hao and Miao, H. and Borkin, D. and Purohit, Trupta and Song, Jiho and Chase, Jennifer and Li, Shuangjiang and Ndoj, Juliano and Kłossowski, Szymon and Kim, EunGi and Mao, Fengbiao and Zhou, Bo and Ropa, James and Krotoska, Marta Z and Jin, Zhuang and Ernst, P. and Feng, Xiaomin and Huang, Gang and Nishioka, K. and Kelly, Sean D. and He, Miao and Wen, Bo and Sun, Duxin and Muntean, Andrew G and Dou, Y. and Maillard, I. and Cierpicki, T. and Grembecka, J.}
}
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. The histone methyltransferase ASH1L plays a role in various diseases, including cancer, and has been validated as a therapeutic target; however, no inhibitors of ASH1L have been reported. Here the authors present small molecule inhibitors of ASH1L and demonstrate their on-target activity in leukemia cells and a mouse model of leukemia.