Targeted degradation of Pin1 shows promise for pancreatic cancer treatment

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.

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.

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."

"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."

The title of the paper is "Targeted Degradation of Pin1 by Protein Destabilizing Compounds."

Source:

University of California - Riverside