The protein made by the ASH1L gene plays a key role in the development of acute leukemia, along with other diseases. The ASH1L protein, however, has been challenging to target therapeutically.Now a team of researchers led by Jolanta Grembecka, PhD, and Tomasz Cierpicki, PhD, 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 leukemia.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 leukemia, the lead compound, known as AS-99, successfully reduced leukemia progression.

“This work points to a new, exiting avenue to develop new therapeutic agents against acute leukemia, 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.