In the evolving field of drug discovery, targeted protein degradation emerges as a powerful technique aimed at selectively dismantling disease-promoting proteins. A collaborative team of scientists from the University of California, Riverside, has crafted a groundbreaking approach to uncover protein degraders specifically targeting Pin1, a pivotal protein implicated in the progression of pancreatic cancer.
The researchers disclosed their findings today in the prestigious Proceedings of the National Academy of Sciences, revealing the design of novel agents that not only exhibit a robust affinity for Pin1 but are meticulously engineered to induce its destabilization and subsequent cellular degradation—an advancement that holds the potential to revolutionize cancer treatment strategies.
Under the able leadership of Maurizio Pellecchia, a professor of biomedical sciences at the UCR School of Medicine, the team discovered that these lab-synthesized degraders function akin to “molecular crowbars,” effectively prying open the structure of Pin1, thereby rendering it prone to instability.
“This innovative ‘molecular crowbar’ strategy presents a compelling avenue in drug discovery and pharmacology,” asserted Pellecchia, who occupies the Daniel Hays Chair in Cancer Research at UCR. “Our agents targeting Pin1 not only exhibit a potent binding capability but also instigate its destabilization, which leads to its degradation across a spectrum of human cancer cell lines. This method could pave the way for the development of agents with enhanced efficacy in targeting and degrading harmful proteins.”
The researchers possess a twofold interest in investigating Pin1. Their goals include identifying robust molecules capable of degrading Pin1 and elucidating the role of Pin1 in the intricate interactions between pancreatic cancer cells and the tumor microenvironment—including macrophages and cancer-associated fibroblasts—where Pin1 is also abundantly expressed. Cancer-associated fibroblasts are critical players in tumor development and progression.
Pin1, a rapid-response enzyme integral to numerous cellular processes, has been linked to tumor formation and is frequently overexpressed in various cancers. Interestingly, its deficiency has been shown to considerably suppress cancer progression. It is notably present at elevated levels in cancer-associated fibroblasts and pancreatic cancer cells.
Pancreatic cancer presents unique treatment challenges due to the dense fibrous tissue enveloping malignant cells. Consequently, this fibrotic barrier significantly impedes the effectiveness of conventional treatments aimed at reaching pancreatic cancer cells. Our objective is to decipher the intricate communication between cancer-associated fibroblasts and pancreatic cancer cells, as we strongly suspect that Pin1 plays a crucial role in this interaction.”
Maurizio Pellecchia, professor of biomedical sciences, UCR School of Medicine
Pellecchia elaborated that successfully targeting and eradicating cancer-associated fibroblasts through Pin1 inhibition could enhance the susceptibility of pancreatic cancer cells to existing anticancer agents. Despite these promising avenues, the challenge has been to develop highly effective and selective Pin1 inhibitors capable of penetrating cancer-associated fibroblasts and cancer cells, while concurrently inhibiting the function of Pin1 and promoting its degradation.
“Our molecular degrader, the ‘crowbar,’ effectively unravels the structural integrity of Pin1, its target,” Pellecchia remarked. “We are energized by this mechanism because of its uniqueness and potential applicability to various drug targets. Inducing cellular degradation is a markedly more efficient strategy to counteract the effects of an overexpressed oncogenic enzyme than mere inhibition.”
Pellecchia is engaged in a collaborative effort with researchers at the City of Hope, supported by a National Cancer Institute grant focused on addressing health disparities in cancer research. This initiative will evaluate the efficacy of the molecular degraders identified by Pellecchia’s team in inhibiting cancer-associated fibroblasts in patients with pancreatic cancer and other gastrointestinal malignancies.
“Our collaboration aims to explore the potential for administering these agents to pancreatic cancer patients or other individuals experiencing peritoneal metastasis, which is frequently linked to the activity of cancer-associated fibroblasts,” Pellecchia stated. “Ultimately, our goal is to advance these agents into innovative cancer therapeutics through this partnership.”
According to Pellecchia, the prospect exists for pharmaceutical companies to formulate therapeutics that effectively induce both the destabilization and degradation of cancer targets.
“This could herald a new modality for targeting future drugs,” he proposed. “Moreover, Pin1 inhibitors capable of inducing the degradation of Pin1 could significantly influence the treatment of a variety of cancers—not exclusively pancreatic cancer—due to their impact on cancer-associated fibroblasts.”
Pellecchia’s research team included Giulia Alboreggia, the paper’s lead author, and Parima Udompholkul from his lab, along with Isaac Rodriguez and Gregor Blaha, the latter of whom works in Blaha’s laboratory.
The groundbreaking research received partial funding from grants provided by the National Institutes of Health.
The title of the published paper is “Targeted Degradation of Pin1 by Protein Destabilizing Compounds.”
Source:
University of California – Riverside
**Interview with Maurizio Pellecchia on New Advances in Targeted Protein Degradation for Pancreatic Cancer Treatment**
**Editor:** Thank you for joining us today, Dr. Pellecchia. Your team’s recent publication in the *Proceedings of the National Academy of Sciences* highlights an innovative approach to combating pancreatic cancer through targeted protein degradation. Can you tell us more about the significance of targeting the protein Pin1?
**Maurizio Pellecchia:** Thank you for having me. Pin1 is a critical player in the progression of pancreatic cancer. It’s overexpressed in many cancers and is involved in various cellular processes, contributing to tumor formation. By specifically targeting and degrading Pin1, we can disrupt its function, which has been shown to significantly suppress cancer progression. Essentially, this offers a new pathway to tackle the complexities of pancreatic cancer treatment.
**Editor:** You refer to your newly developed agents as “molecular crowbars.” Could you explain this concept and how it functions in the degradation of Pin1?
**Maurizio Pellecchia:** Absolutely. The term “molecular crowbar” describes how our agents work to pry open and destabilize the Pin1 protein. These novel compounds bind fiercely to Pin1 and unravel its structure, making it unstable and leading to its degradation within cancer cells. This mechanism represents a more efficient strategy than traditional methods of inhibition, as it actively eradicates the problematic protein rather than just blocking its function.
**Editor:** The interactions between cancer-associated fibroblasts and pancreatic cancer cells are well-documented challenges in treatment. How does your research address these interactions, and what role does Pin1 play in this context?
**Maurizio Pellecchia:** That’s a great question. The fibrous tissue surrounding pancreatic cancer cells creates a significant barrier to treatment. We are investigating how Pin1 mediates the communication between pancreatic cancer cells and surrounding fibroblasts, which are vital for tumor development. By inhibiting Pin1, we believe we can alter this interaction and make cancer cells more susceptible to existing treatments, potentially improving therapeutic outcomes.
**Editor:** Alongside the development of these agents, you mentioned collaboration with researchers at the City of Hope and tackling health disparities in cancer research. How does this collaboration enhance your research?
**Maurizio Pellecchia:** Collaboration is vital in cancer research. By working with the City of Hope, we can share insights and resources, which enhances our understanding of cancer biology and treatment strategies. The support from the National Cancer Institute also allows us to address cancer disparities, ensuring that everyone benefits from the advances we are making in targeted therapies and drug development.
**Editor:** what are your next steps in this research, and what potential impact do you foresee this could have on future cancer treatments?
**Maurizio Pellecchia:** We are focused on fine-tuning our agents to ensure they are highly effective and selective in targeting Pin1 across different cell types. If successful, this could radically improve how we approach pancreatic cancer, offering hope for more effective treatments. Beyond pancreatic cancer, our strategy of inducing protein degradation could be applied to various other oncogenic proteins, potentially transforming the landscape of cancer therapy as we know it.
**Editor:** Thank you, Dr. Pellecchia, for sharing your insights with us. This is indeed an exciting development in cancer research, and we look forward to seeing the results of your ongoing work.
**Maurizio Pellecchia:** Thank you for having me. It’s an exciting time in the field, and I appreciate the opportunity to share our findings.
