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 today 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.
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 could degrade Pin1. They also wanted to study the role of Pin1 in the crosstalk between pancreatic cancer cells and the tumor microenvironment -; macrophages and cancer-associated fibroblasts -; where Pin 1 is also expressed. Macrophages are a type of white blood cell. Cancer-associated fibroblasts are cells that play a key role in the development and progression of tumors.
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. 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."
Maurizio Pellecchia, professor of biomedical sciences, UCR School of Medicine
Pellecchia explained that if his team can kill cancer-associated fibroblasts through Pin1 inhibition, then it is possible that pancreatic cancer cells will be more susceptible to anticancer agents. 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, possibly eliminating Pin1 altogether by inducing its degradation.
"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 addresses health disparities in cancer research. The effort 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."
Pellecchia was joined in the research by Giulia Alboreggia, the first author of the paper, and Parima Udompholkul, who work in his laboratory; and Isaac Rodriguez and Gregor Blaha. Rodriguez works in Blaha's laboratory.
The research was supported in part by grants from the National Institutes of Health.
The title of the paper is "Targeted Degradation of Pin1 by Protein Destabilizing Compounds."
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