Leukemia stem cells are rare cells that can renew themselves while continuing to generate malignant cells known as leukemic blasts. These cells are difficult to eradicate using chemotherapy drugs and frequently lead to recurrence of leukemia.
Leukemia stem cells, however, are dependent on a protein complex called polycomb repressive complex 1, or PRC1, which interacts with chromatin and turns genes off.
Now a team of researchers led by Tomasz Cierpicki, Ph.D., and Jolanta Grembecka, Ph.D., from the University of Michigan has developed the first small-molecule inhibitors of PRC1 -; a first step toward developing a potential new therapeutic approach to treating acute myeloid leukemia by shutting down the activity of leukemia stem cells.
These inhibitors demonstrate activity in leukemia cells and patient samples, as reported in Nature Chemical Biology, and also open new opportunities to study the development of leukemia at the molecular level.
Our lead compound, RB-3, represents an attractive and unique agent for studying PRC1 biology. This work demonstrates that directly targeting the activity of PRC1 is indeed feasible and could lay the groundwork for the development of new pharmaceutical agents for leukemia and possibly other cancers."
Tomasz Cierpicki, Associate Professor, Biophysics and Pathology, University of Michigan
Shukla, S., et al. (2021) Small-molecule inhibitors targeting Polycomb repressive complex 1 RING domain. Nature Chemical Biology. doi.org/10.1038/s41589-021-00815-5.