Targeted Degradation of Pin1 by an Antagonistic Peptide Enhance Gemcitabine Therapy in Pancreatic Cancer

Abstract

Targeted protein degradation (TPD) has emerged as a powerful strategy for eliminating disease-causing proteins. The prolyl isomerase Pin1 is an attractive therapeutic target given its oncogenic function. Here, we develop PIPWF, a novel peptide degrader that induces Pin1 degradation through multivalent binding and conformational destabilization. Pin1 degradation attenuates cancer-associated fibroblasts (CAFs) activation to reshape the fibrotic tumor microenvironment and enhance chemosensitivity via ENT1-mediated gemcitabine uptake. In vivo results demonstrated that both PIPWF and its nanoformulation M-PIPWF synergized with gemcitabine to induce tumor regression and prolong survival, illustrating a novel peptide-based TPD strategy against Pin1-driven malignancies.