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Pre-clinical evaluation of a potent and effective Pin1-degrading agent in pancreatic cancer
Giulia Alboreggia1, Tiane Li2, Anne Marie Prentiss1
1Division of Biomedical Sciences, School of Medicine, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA.
Abstract:
The peptidyl-prolyl isomerase protein Pin1 has been shown to contribute to cancer onset, development, and progression by regulating the function and stability of oncogenes and tumor suppressors, both in cancer cells and surrounding stromal cells. Hence, it has long been sought as a possible therapeutic target in oncology. However, further validation of Pin1 as a suitable target for novel therapeutic strategies requires the development of potent and effective pharmacological inhibitors, which are currently scarce. Very recently, we reported novel covalent Pin1 inhibitors that, acting as molecular crowbars, destabilize the protein in vitro, causing its degradation in cells. Here, we advanced those agents by improving their plasma stability. We further characterized their mode of action on cancer cells and cancer-associated fibroblasts and studied their efficacy in a syngeneic mouse model of pancreatic cancer peritoneal metastases. Our studies support the hypothesis that these novel Pin1 degraders could be translated into effective therapeutics against peritoneal metastases in pancreatic and other types of gastrointestinal and abdominal cancers that develop peritoneal metastases.
Insights
Novel covalent inhibitors targeting peptidyl-prolyl isomerase (Pin1) show promise for treating pancreatic cancer peritoneal metastases. These improved Pin1 degraders enhance drug stability and efficacy, offering a potential new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Peptidyl-prolyl isomerase (Pin1) is implicated in cancer progression by regulating oncogenes and tumor suppressors.
- Pin1 is a validated therapeutic target in oncology, but effective inhibitors are scarce.
- Previous work identified covalent Pin1 inhibitors acting as molecular crowbars to induce protein degradation.
Purpose of the Study:
- To enhance the plasma stability of novel covalent Pin1 inhibitors.
- To further characterize the mechanism of action of these inhibitors in cancer cells and fibroblasts.
- To evaluate the efficacy of these improved Pin1 degraders in a preclinical model of pancreatic cancer peritoneal metastases.
Main Methods:
- Chemical modification of existing covalent Pin1 inhibitors to improve plasma stability.
- In vitro and cellular assays to assess inhibitor mode of action and degradation of Pin1.
- In vivo studies using a syngeneic mouse model of pancreatic cancer peritoneal metastases.
Main Results:
- The advanced covalent Pin1 inhibitors demonstrated improved plasma stability compared to previous agents.
- These compounds effectively destabilized Pin1 and induced its degradation in cancer cells and cancer-associated fibroblasts.
- The novel Pin1 degraders showed significant therapeutic efficacy against pancreatic cancer peritoneal metastases in mice.
Conclusions:
- The enhanced covalent Pin1 inhibitors represent a promising class of therapeutics.
- These agents have potential for treating peritoneal metastases in pancreatic, gastrointestinal, and abdominal cancers.
- Further development of these Pin1 degraders could lead to effective clinical treatments for peritoneal carcinomatosis.
