A group of scientists from the University of California, Riverside, has developed an innovative technique to discover protein degraders that specifically target Pin1, a protein that plays a role in the development of pancreatic cancer.
In the field of drug discovery, a method called targeted protein degradation selectively removes proteins that cause diseases. A research team at the University of California, Riverside, has taken a novel approach to identify protein degraders that aim at Pin1, a protein linked to pancreatic cancer.
In their findings published in the Proceedings of the National Academy of Sciences, the team revealed the creation of agents that bind tightly to Pin1 and are engineered to destabilize and degrade it at the cellular level, opening up possibilities for new cancer treatment options.
The project, led by Maurizio Pellecchia, a professor of biomedical sciences in the UCR School of Medicine, produced degraders that function like “molecular crowbars,” altering the structure of Pin1 and making it less stable.
“This ‘molecular crowbar’ approach shows promise as a new strategy in drug discovery and pharmacology,” said Pellecchia, who holds the Daniel Hays Chair in Cancer Research at UCR. “Our agents effectively bind to Pin1, destabilizing it, which leads to its degradation in various human cancer cell lines. This method could lead to the development of drugs that more efficiently target and eliminate harmful proteins.”
The researchers had a dual interest in Pin1. They aimed to find effective molecules that could degrade it and to explore how Pin1 interacts with pancreatic cancer cells and the surrounding tumor microenvironment, which includes macrophages and cancer-associated fibroblasts, both of which also express Pin1. Macrophages are a type of white blood cell, while cancer-associated fibroblasts help tumors develop and grow.
Pin1 is a rapidly acting enzyme involved in numerous cellular activities and is known to contribute to tumor development. It is often overproduced in tumors, and its reduction can significantly slow cancer progression. In pancreatic cancer cells and cancer-associated fibroblasts, its levels are particularly high.
“One reason pancreatic cancer is hard to treat is that a dense tissue layer surrounds the cancer cells, making it challenging for treatments to effectively reach them,” Pellecchia explained. “We want to investigate the interactions between cancer-associated fibroblasts and pancreatic cancer cells, as we think Pin1 is an integral part of that communication.”
Pellecchia indicated that successfully inhibiting Pin1 in cancer-associated fibroblasts could make pancreatic cancer cells more vulnerable to treatment. However, the challenge has been to create potent and selective Pin1 inhibitors that are capable of penetrating both cancer-associated fibroblasts and cancer cells while blocking Pin1’s function, ideally leading to its complete degradation.
“Our molecular degrader, the ‘crowbar,’ opens up the structure of Pin1, which is our target,” Pellecchia noted. “This mechanism excites us because we feel it is unique and might be relevant for targeting other proteins as well. Causing cellular degradation is a more powerful method to counteract an overactive oncogenic enzyme than merely inhibiting its activity.”
Pellecchia is collaborating with researchers from the City of Hope as part of a National Cancer Institute grant focused on addressing health disparities in cancer research. This collaboration aims to evaluate how effectively the molecular degraders discovered by Pellecchia’s team inhibit cancer-associated fibroblasts in patients with pancreatic and other gastrointestinal cancers.
“Our goal is to see if we can administer these agents to pancreatic cancer patients or others who develop peritoneal metastasis, which frequently involves activity from cancer-associated fibroblasts,” Pellecchia stated. “In the long run, we aspire to transform our agents into innovative cancer therapies through this partnership.”
Pellecchia suggests that there is potential for pharmaceutical companies to create therapies that not only destabilize their targets but also lead to their degradation.
“This represents a new possible strategy for future drug formulations,” he indicated. “Moreover, Pin1 inhibitors that ensure effective degradation could significantly impact several cancers beyond just pancreatic cancer due to their influence on cancer-associated fibroblasts.”
Pellecchia’s research team included Giulia Alboreggia, the paper’s first author, and Parima Udompholkul from his lab, as well as Isaac Rodriguez and Gregor Blaha, with Rodriguez working in Blaha’s lab.
This research received partial funding from the National Institutes of Health.
