Systematic Optimization of Proteolysis-Targeting Chimeras for PIN1 Enables Selective Degradation and Antitumor Activity In Vivo

<b>Background</b>: The peptidyl-prolyl cis-trans isomerase PIN1 regulates multiple oncogenic and tumor-suppressive pathways and is frequently overexpressed in human cancers. Although pharmacological inhibition of PIN1 has shown antitumor potential, existing PIN1-targeting degraders lack systematic structure-activity relationship (SAR) analyses and display inconsistent cellular efficacy, leaving the therapeutic relevance of PIN1 degradation unclear. <b>Methods</b>: Two series of PIN1-targeting PROTACs were designed using the covalent inhibitor sulfopin as the PIN1 binder and ligands for either cereblon (CRBN) or von Hippel-Lindau (VHL). Systematic SAR studies focused on linker structure and jointing atom composition. PIN1 degradation was assessed by Western blotting in multiple cancer cell lines, and further investigated through a series of computational and mechanistic experiments. Antitumor efficacy and safety were evaluated in an MCF-7 xenograft mouse model with preliminary pharmacokinetic analysis. <b>Results</b>: SAR analysis revealed that short, linear linkers and reduced hydrogen bond donor content markedly enhanced PIN1 degradation, whereas VHL-recruiting PROTACs showed inferior cellular activity. These studies identified <b>PC2</b>, a CRBN-recruiting PROTAC, as a lead compound. <b>PC2</b> selectively induced ubiquitin-proteasome-dependent PIN1 degradation with minimal global proteomic or transcriptomic perturbation. Despite modest antiproliferative effects in vitro, <b>PC2</b> significantly suppressed tumor growth in vivo without observable toxicity and achieved effective intratumoral PIN1 degradation. <b>Conclusions</b>: This study defines SAR-guided design principles for PIN1-targeting PROTACs and demonstrates that selective PIN1 degradation can produce robust antitumor activity in vivo. <b>PC2</b> represents the first PIN1 degrader validated in animal models and supports targeted PIN1 degradation as a viable anticancer strategy.