{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T09:01:32Z","timestamp":1785142892352,"version":"3.55.0"},"reference-count":39,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":32,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The phosphatidylinositol 3\u2010kinase (PI3K) pathway is frequently hyperactivated in cancers, promoting tumor growth and resistance to conventional therapies. Conventional PI3K inhibitors often suffer from poor tumor selectivity, systemic toxicity, and the development of acquired resistance. To overcome these issues, we have designed multifunctional peptide\u2010drug conjugates (PDCs) utilizing chaperone\u2010mediated autophagy (CMA), a selective lysosomal degradation mechanism, for precise targeting of PI3K. Our approach began with the development of a lead compound, CC\u20103, derived from Copanlisib and incorporating a CMA\u2010recognition motif (KFERQ\u2010like sequence). We further enhanced this compound by creating TCCC\u20101, integrating a tumor\u2010homing peptide (Thx) and a cell\u2010penetrating peptide (T2) to improve cellular uptake and specificity. In vitro studies revealed that TCCC\u20101 effectively induced PI3K degradation, inhibited downstream pAkt signaling, and promoted apoptosis alongside G2\/M cell cycle arrest in non\u2010small cell lung cancer (NSCLC) cells, including those resistant to Copanlisib. In vivo experiments using NCI\u2010H460 xenograft models demonstrated that TCCC\u20101 achieved up to 97.0% tumor suppression at high doses, surpassing the efficacy of Copanlisib, without causing significant systemic toxicity, organ damage, or metabolic disturbances such as hyperglycemia. These results highlight TCCC\u20101 as a promising therapeutic candidate that leverages CMA for precise PI3K degradation, offering enhanced penetration and selectivity against tumors.<\/jats:p>","DOI":"10.1002\/ardp.70289","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T12:41:01Z","timestamp":1783082461000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chaperone\u2010Mediated Autophagy\u2010Directed Degradation of PI3K in Tumor Cells: Development of Multifunctional Peptide\u2010Drug Conjugates With Enhanced Penetration and Selectivity"],"prefix":"10.1002","volume":"359","author":[{"given":"Chenyu","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Respiratory Disease, Guangzhou Key Laboratory of Tuberculosis Research, Department of Pharmacy, Guangzhou Chest Hospital, Institute of Tuberculosis Guangzhou Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honglan","family":"Zhong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Respiratory Disease, Guangzhou Key Laboratory of Tuberculosis Research, Department of Pharmacy, Guangzhou Chest Hospital, Institute of Tuberculosis Guangzhou Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Respiratory Disease, Guangzhou Key Laboratory of Tuberculosis Research, Department of Pharmacy, Guangzhou Chest Hospital, Institute of Tuberculosis Guangzhou Medical University Guangzhou China"},{"name":"Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target &amp; Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital Guangzhou Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenjian","family":"Xing","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Respiratory Disease, Guangzhou Key Laboratory of Tuberculosis Research, Department of Pharmacy, Guangzhou Chest Hospital, Institute of Tuberculosis Guangzhou Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Liu","sequence":"additional","affiliation":[{"name":"Analytical Applications Center, Shimadzu (China) Co. 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