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 journalArticlepeer-review

15 Scopus citations


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 languageEnglish (US)
Article number2792
JournalNature communications
Issue number1
StatePublished - Dec 1 2021
Externally publishedYes

ASJC Scopus subject areas

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


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