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Although pharmacological inhibition of PIN1 has shown antitumor potential, existing PIN1-targeting degraders lack systematic structure\u2013activity 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\u2013Lindau (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\u2013proteasome-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.<\/jats:p>","DOI":"10.3390\/pharmaceutics18030288","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T13:58:03Z","timestamp":1772114283000},"page":"288","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Systematic Optimization of Proteolysis-Targeting Chimeras for PIN1 Enables Selective Degradation and Antitumor Activity In Vivo"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4218-9297","authenticated-orcid":false,"given":"Yuying","family":"Ma","sequence":"first","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Teng","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjin","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University, Chongqing 400016, China"},{"name":"Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuke","family":"Deng","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingbo","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruichen","family":"Gao","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingyu","family":"Peng","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University, Chongqing 400016, China"},{"name":"Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1673-2826","authenticated-orcid":false,"given":"Yue","family":"Wei","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University, Chongqing 400016, China"},{"name":"Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6185-4999","authenticated-orcid":false,"given":"Linfeng","family":"Li","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University, Chongqing 400016, China"},{"name":"Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zufeng","family":"Guo","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University, Chongqing 400016, China"},{"name":"Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/nrc.2016.49","article-title":"The isomerase PIN1 controls numerous cancer-driving pathways and is a unique drug target","volume":"16","author":"Zhou","year":"2016","journal-title":"Nat. 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