Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-23152-6
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Funding
- National Institute of Health (NIH) [1R01 CA244254, 1R01 CA201204, 5R01 CA160467]
- LLS Scholar [1215-14]
- LLS TRP grants [6485-16, 6579-20, 6111-14, 6564-19]
- LLS Screen to Lead grant [8017-20]
- NIH T32 training grant [T32DK007519]
- DOE Office of Science [DE-AC02-06CH11357]
- Michigan Economic Development Corporation
- Michigan Technology Tri-Corridor [085P1000817]
- NIH [1R01 CA226759, 1R01 CA207272, 1R01 AG050509]
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The study developed small molecule inhibitors of the ASH1L histone methyltransferase, which bind to the autoinhibitory loop region in the SET domain. The lead compound AS-99 demonstrated on-target activity in leukemia cells by inducing apoptosis and differentiation, and reducing leukemia burden in vivo.
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.
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