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To tackle the issues, we have devised a photo\u2010click proteolysis targeting chimera (PCPTAC) that enables spatiotemporally controllable intracellular synthesis of PROTACs by photo\u2010triggered bioorthogonal ligation. A photocaged dibenzosilacycloheptyne (photo\u2010DBSH) and the complementary azide were deployed to tag the oncoprotein ligands (i.e., (+)\u2010JQ1 for BRD4 and Olaparib for PARP1) and the E3 ligase ligand (i.e., Pomalidomide for CRBN), respectively, for a proof\u2010of\u2010concept study and potential treatment for triple\u2010negative breast cancer (TNBC). Upon light irradiation, photo\u2010DBSH\u2010JQ1\/\u2010Olap was rapidly uncaged to give the reactive cycloalkyne\u2010JQ1\/\u2010Olap, which immediately underwent a strain\u2010promoted azide\u2013alkyne cycloaddition with azide\u2010Pomalidomide, in situ generating dual PROTACs for simultaneous degradation of BRD4 and PARP1 in TNBC MDA\u2010MB\u2010231 cells, with 25\u2010 and 2.4\u2010fold more potent antiproliferative activity than the un\u2010irradiated inhibitors and the corresponding PROTAC combination, respectively (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u00a0=\u00a00.032\u00a0\u00b5M vs. 0.846\u00a0\u00b5M and 0.075\u00a0\u00b5M). Further in zebrafish models, PCPTAC promoted BRD4 degradation leading to thinner yolk sac extension and achieved 94% tumor inhibition in HeLa xenografts. This split\u2010and\u2010photoclick strategy paves a new avenue for developing safer and more efficacious PROTACs with synergistic antitumor effects.\n                  <\/jats:p>","DOI":"10.1002\/anie.202518897","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T06:09:21Z","timestamp":1777010961000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Photo\u2010click Proteolysis\u2010Targeting Chimeras Enable Intracellular Generation of PROTACs for Precise Dual Protein Degradation"],"prefix":"10.1002","volume":"65","author":[{"given":"Jing","family":"Pang","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery Institute of Thoracic Surgery The First Affiliated Hospital of Soochow University  Suzhou China"},{"name":"Laboratory of Medicinal Chemical Biology Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development College of Pharmaceutical Sciences Suzhou Medical College of Soochow University  Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shihong","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemical Biology Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development College of Pharmaceutical Sciences Suzhou Medical College of Soochow University  Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemical Biology Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development College of Pharmaceutical Sciences Suzhou Medical College of Soochow University  Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyu","family":"Jia","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemical Biology Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development College of Pharmaceutical Sciences Suzhou Medical College of Soochow University  Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8405-7957","authenticated-orcid":false,"given":"Ya\u2010Qiu","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery Institute of Thoracic Surgery The First Affiliated Hospital of Soochow University  Suzhou China"},{"name":"Laboratory of Medicinal Chemical Biology Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development College of Pharmaceutical Sciences Suzhou Medical College of Soochow University  Suzhou 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