Targeted protein degradation is a method that selectively eliminates disease-causing proteins. Scientists at the University of California, Riverside (UCR), are now using this method to pave a way for new cancer therapies. The scientists have developed a “molecular crowbar” strategy to identify protein degraders that target Pin1, a protein involved in pancreatic cancer development. The scientists designed agents that bind tightly to Pin1 and are designed to cause its destabilization and cellular degradation. The degraders which were made in the lab, act like “molecular crowbars” that open up the structure of Pin1, rendering it less stable.
The study is published in the Proceedings of the National Academy of Sciences and led by Maurizio Pellecchia, PhD, a professor of biomedical sciences in the UCR School of Medicine.
“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.”
Pin1 is a fast-acting enzyme involved in many cellular processes and implicated in the formation of tumors. It is overexpressed in many tumors and its deficiency significantly suppresses cancer progression. Its expression level is much higher in cancer-associated fibroblasts and in pancreatic cancer cells.
“Pancreatic cancer is particularly difficult to treat because a highly fibrous tissue covers pancreatic cancer cells,” Pellecchia said. “As a result, it is difficult for treatments to reach the pancreatic cancer cells effectively. We want to understand the crosstalk between cancer-associated fibroblasts and pancreatic cancer cells. We believe Pin1 may play a major role in this cross-talk.”
The difficulty until now, Pellecchia said, has been how to obtain potent and selective Pin1 inhibitors that can penetrate cancer-associated fibroblasts and/or cancer cells and, at the same time, block the function of Pin1.
“Our molecular degrader, the ‘crowbar,’ opens up the structure of Pin1, its target,” Pellecchia said. “We are excited about this mechanism because we believe it’s unique and could be applicable to other drug targets. Inducing its cellular degradation is a much more effective way to counteract the activity of an overexpressed oncogenic enzyme than simply inhibiting it.”
Pellecchia is collaborating with researchers at the City of Hope under a National Cancer Institute collaborative grant that will assess how well the molecular degraders Pellecchia’s team identified inhibit cancer-associated fibroblasts in patients affected by pancreatic cancer and other gastrointestinal cancers.
“Our collaboration would like to see if we can administer these agents to pancreatic cancer patients or other patients that develop peritoneal metastasis, which is often associated with cancer-associated fibroblast activity,” Pellecchia said. “Ultimately, we hope to develop our agents into novel cancer therapeutics in this collaboration.”
According to Pellecchia, it may be possible for pharmaceutical companies to develop therapeutics that can cause both destabilization of the target and its degradation.
“This is a new potential target modality for future drugs,” he said. “Also, Pin1 inhibitors that can cause Pin1 degradation very effectively could have a major impact in a number of cancers, and not just pancreatic cancer, because of their effect on cancer-associated fibroblasts.”
