Background: 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. Methods: 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. Results: 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 PC2, a CRBN-recruiting PROTAC, as a lead compound. PC2 selectively induced ubiquitin–proteasome-dependent PIN1 degradation with minimal global proteomic or transcriptomic perturbation. Despite modest antiproliferative effects in vitro, PC2 significantly suppressed tumor growth in vivo without observable toxicity and achieved effective intratumoral PIN1 degradation. Conclusions: This study defines SAR-guided design principles for PIN1-targeting PROTACs and demonstrates that selective PIN1 degradation can produce robust antitumor activity in vivo. PC2 represents the first PIN1 degrader validated in animal models and supports targeted PIN1 degradation as a viable anticancer strategy.

Target-guided screening of fragments (TGSOF) was developed and employed in the identification of EV-A71 3C protease (3C ^pro ) inhibitors.

A three‐dimensional quantitative structure‐activity relationships model of enterovirus A71 3C protease inhibitors was constructed in this study. The protein‐ligand interaction fingerprint was analyzed to generate a pharmacophore model. A predictive and reliable three‐dimensional quantitative structure‐activity relationships model was built based on the Flexible Alignment of AutoGPA. Moreover, three novel compounds (I–III) were designed and evaluated for their biochemical activity against 3C protease and anti‐enterovirus A71 activity in vitro. III exhibited excellent inhibitory activity (IC₅₀ = 0.031 ± 0.005 μM, EC₅₀ = 0.036 ± 0.007 μM). Thus, this study provides a useful quantitative structure‐activity relationships model to develop potent inhibitors for enterovirus A71 3C protease.