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; Eun Gi 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; Jolanta Grembecka

doi:10.1038/s41467-021-23152-6

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, Eun Gi Kim, Fengbiao Mao, Bo Zhou, James Ropa, Marta Z. Krotoska, Zhuang Jin, Patricia Ernst, Xiaomin Feng, Gang HuangKenichi Nishioka, Samantha Kelly, Miao He, Bo Wen, Duxin Sun, Andrew Muntean, Yali Dou, Ivan Maillard, Tomasz Cierpicki, Jolanta Grembecka

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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.

Original language	English (US)
Article number	2792
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-23152-6
State	Published - Dec 1 2021
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Rogawski, D. S., Deng, J., Li, H., Miao, H., Borkin, D., Purohit, T., Song, J., Chase, J., Li, S., Ndoj, J., Klossowski, S., Kim, E. G., Mao, F., Zhou, B., Ropa, J., Krotoska, M. Z., Jin, Z., Ernst, P., Feng, X., ... Grembecka, J. (2021). Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity. Nature communications, 12(1), Article 2792. https://doi.org/10.1038/s41467-021-23152-6

Rogawski, DS, Deng, J, Li, H, Miao, H, Borkin, D, Purohit, T, Song, J, Chase, J, Li, S, Ndoj, J, Klossowski, S, Kim, EG, Mao, F, Zhou, B, Ropa, J, Krotoska, MZ, Jin, Z, Ernst, P, Feng, X, Huang, G, Nishioka, K, Kelly, S, He, M, Wen, B, Sun, D, Muntean, A, Dou, Y, Maillard, I, Cierpicki, T & Grembecka, J 2021, 'Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity', Nature communications, vol. 12, no. 1, 2792. https://doi.org/10.1038/s41467-021-23152-6

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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.",

author = "Rogawski, {David S.} and Jing Deng and Hao Li and Hongzhi Miao and Dmitry Borkin and Trupta Purohit and Jiho Song and Jennifer Chase and Shuangjiang Li and Juliano Ndoj and Szymon Klossowski and Kim, {Eun Gi} and Fengbiao Mao and Bo Zhou and James Ropa and Krotoska, {Marta Z.} and Zhuang Jin and Patricia Ernst and Xiaomin Feng and Gang Huang and Kenichi Nishioka and Samantha Kelly and Miao He and Bo Wen and Duxin Sun and Andrew Muntean and Yali Dou and Ivan Maillard and Tomasz Cierpicki and Jolanta Grembecka",

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AU - Li, Hao

AU - Miao, Hongzhi

AU - Borkin, Dmitry

AU - Purohit, Trupta

AU - Song, Jiho

AU - Chase, Jennifer

AU - Li, Shuangjiang

AU - Ndoj, Juliano

AU - Klossowski, Szymon

AU - Kim, Eun Gi

AU - Mao, Fengbiao

AU - Zhou, Bo

AU - Ropa, James

AU - Krotoska, Marta Z.

AU - Jin, Zhuang

AU - Ernst, Patricia

AU - Feng, Xiaomin

AU - Huang, Gang

AU - Nishioka, Kenichi

AU - Kelly, Samantha

AU - He, Miao

AU - Wen, Bo

AU - Sun, Duxin

AU - Muntean, Andrew

AU - Dou, Yali

AU - Maillard, Ivan

AU - Cierpicki, Tomasz

AU - Grembecka, Jolanta

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N2 - 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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Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity

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