In drug discovery, targeted protein degradation is a method that selectively eliminates disease-causing proteins. A University of California, Riverside team of scientists has used a novel approach to identify protein degraders that target Pin1, a protein involved in pancreatic cancer development. The team reports in the Proceedings of the National Academy of Sciences that it has designed agents that not only bind tightly to Pin1 but are designed to cause its destabilization and cellular degradation—a finding that could pave the way for new cancer therapies.
The title of the paper is "Targeted Degradation of Pin1 by Protein Destabilizing Compounds." Led by Maurizio Pellecchia, a professor of biomedical sciences in the UCR School of Medicine, the team found that the degraders, which were made in the lab, act like "molecular crowbars" that open up the structure of Pin1, rendering it less stable. "This 'molecular crowbar' strategy is potentially a promising method in drug discovery and pharmacology," said Pellecchia, who holds the Daniel Hays Chair in Cancer Research at UCR.
"Our agents targeting Pin1 not only potently bind to Pin1 but also destabilize it and this destabilization leads to its degradation across various human cancer cell lines. This strategy could offer an additional pathway for developing agents that can more effectively target and degrade harmful proteins." The researchers' interest in studying Pin1 was two-fold.
They wanted to identify potent molecules that c.