1 min readResearchers Develop First-in-Class Inhibitors Against Key Leukaemia Protein

Ann Arbor, MI — The protein made by the ASH1L gene plays a key role in the development of acute leukaemia, along with other diseases. The ASH1L protein, however, has been challenging to target therapeutically.

Now a team of researchers led by Dr. Jolanta Grembecka and Dr. Tomasz Cierpicki, from the University of Michigan has developed first-in-class small molecules to inhibit ASH1L’s SET domain — preventing critical molecular interactions in the development and progression of leukaemia.

The team’s findings, which used fragment-based screening, followed by medicinal chemistry and a structure-based design, appear in Nature Communications.

In mouse models of mixed lineage leukaemia, the lead compound, known as AS-99, successfully reduced leukaemia progression.

“This work points to a new, exiting avenue to develop new therapeutic agents against acute leukaemia, as well as providing a new approach to further study the biological functions of ASH1L and its role in the development of the disease,” says Grembecka, associate professor of pathology at Michigan Medicine and co-director of the developmental therapeutics program at the U-M Rogel Cancer Center. 

The study was a close collaboration between her lab and the lab of co-senior author Cierpicki, an associate professor of biophysics and pathology.

Article adapted from a Michigan Medicine, University of Michigan news release.

Publication: Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity. Rogawski, DS et al. Nature Communications (May 14, 2021): Click here to view.

ASH1L, Leukaemia

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