May 14, 2021 5:00 AM

Researchers Develop First-in-Class Inhibitors Against Key Leukemia Protein

Approach opens a new avenue to study the biology of acute leukemia and for the development of new drugs.

protein in pink and blue an light grey with lab note badge spelled out on bottom right in yellow background and navy font
An X-ray crystallography image showing an ASH1L inhibitor developed at U-M in complex with the protein.

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, Ph.D., and Tomasz Cierpicki, Ph.D., 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.

Paper citied: “Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity,” Nature Communications. DOI:10.1038/s41467-021-23152-6