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.

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Materials provided by Michigan Medicine - University of Michigan. Original written by Ian Demsky. Note: Content may be edited for style and length.

Journal Reference:

1. David S. Rogawski, Jing Deng, Hao Li, Hongzhi Miao, Dmitry Borkin, Trupta Purohit, Jiho Song, Jennifer Chase, Shuangjiang Li, Juliano Ndoj, Szymon Klossowski, EunGi Kim, Fengbiao Mao, Bo Zhou, James Ropa, Marta Z. Krotoska, Zhuang Jin, Patricia Ernst, Xiaomin Feng, Gang Huang, Kenichi Nishioka, Samantha Kelly, Miao He, Bo Wen, Duxin Sun, Andrew Muntean, Yali Dou, Ivan Maillard, Tomasz Cierpicki, Jolanta Grembecka. Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity. Nature Communications, 2021; 12 (1) DOI: 10.1038/s41467-021-23152-6