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Proteasome inhibitors that target the catalytic subunits within the 20S have proven to be valuable research tools and therapeutics for various cancers. Herein we report the discovery of rapaprotin, a 26S proteasome assembly inhibitor from our natural product\u2010inspired hybrid macrocycle rapafucin library. Rapaprotin induces apoptosis in both myeloma and leukemia cell lines. Genome\u2010wide CRISPR\u2010Cas9 screen identified a cytosolic enzyme, prolyl endopeptidase (PREP) that is required for the pro\u2010apoptotic activity of rapaprotin. Further mechanistic studies revealed that rapaprotin acts as a molecular transformer, changing from an inactive cyclic form into an active linear form, rapaprotin\u2010L, upon PREP cleavage, to block 26S proteasome activity. Time\u2010resolved cryogenic electron microscopy (cryo\u2010EM) revealed that rapaprotin\u2010L induces dissociation of the 19S RP from the 26S holoenzyme, which was verified in cells. Furthermore, rapaprotin exhibits a marked synergistic effect with FDA\u2010approved proteasome inhibitors and resensitizes drug\u2010resistant multiple myeloma cells from patients to bortezomib. Taken together, these results suggest that rapaprotin is a new chemical tool to probe the dynamics of the 26S proteasome assembly and a promising anticancer drug lead.<\/jats:p>","DOI":"10.1002\/anie.202500288","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T12:18:31Z","timestamp":1758111511000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Rapaprotin, an Endopeptidase\u2010Activated Proteasome Inhibitor that Induces 26S Disassembly"],"prefix":"10.1002","volume":"64","author":[{"given":"Hanjing","family":"Peng","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Molecular Sciences Johns Hopkins School of Medicine  Baltimore MD 21205 USA"},{"name":"The SJ Yan and HJ Mao Laboratory of Chemical Biology Johns Hopkins School of Medicine  Baltimore MD 21205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zufeng","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Molecular Sciences Johns Hopkins School of Medicine  Baltimore MD 21205 USA"},{"name":"The SJ Yan and HJ Mao Laboratory of Chemical Biology Johns Hopkins School of Medicine  Baltimore MD 21205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei Li","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Artificial Microstructures and Mesoscopic Physics Laboratory of Electron Microscopy School of Physics Peking University  Beijing 100871 China"},{"name":"Bioentropy Inc  Cambridge MA 02138 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deyao","family":"Yin","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Artificial Microstructures and Mesoscopic Physics Laboratory of Electron Microscopy School of Physics Peking University  Beijing 100871 China"},{"name":"Peking\u2010Tsinghua Joint Center for Life Sciences Peking University  Beijing 100871 China"},{"name":"AI for Science (AI4S)\u2010Preferred Program School of Chemical Biology and Biotechnology Peking University  Shenzhen 518055 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shitao","family":"Zou","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Artificial Microstructures and Mesoscopic Physics Laboratory of Electron Microscopy School of Physics Peking University  Beijing 100871 China"},{"name":"Peking\u2010Tsinghua Joint Center for Life Sciences Peking University  Beijing 100871 China"},{"name":"AI for Science (AI4S)\u2010Preferred Program School of Chemical Biology and Biotechnology Peking University  Shenzhen 518055 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Asbell","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Molecular Sciences Johns Hopkins School of Medicine  Baltimore MD 21205 USA"},{"name":"The SJ Yan and HJ Mao Laboratory of Chemical Biology Johns Hopkins School of Medicine  Baltimore MD 21205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett R.","family":"Ullman","sequence":"additional","affiliation":[{"name":"Rapafusyn Pharmaceuticals  Baltimore MD 21205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Thakar","sequence":"additional","affiliation":[{"name":"Sidney Kimmel Comprehensive Cancer Center Johns Hopkins School of Medicine Baltimore MD 21287 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feiran","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Molecular Sciences Johns Hopkins School of Medicine  Baltimore MD 21205 USA"},{"name":"The SJ Yan and HJ Mao Laboratory of Chemical Biology Johns Hopkins School of Medicine  Baltimore MD 21205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam Y.","family":"Hong","sequence":"additional","affiliation":[{"name":"Rapafusyn Pharmaceuticals  Baltimore MD 21205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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Subba","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Molecular Sciences Johns Hopkins School of Medicine  Baltimore MD 21205 USA"},{"name":"The SJ Yan and HJ Mao Laboratory of Chemical Biology Johns Hopkins School of Medicine  Baltimore MD 21205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunyu","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Artificial Microstructures and Mesoscopic Physics Laboratory of Electron Microscopy School of Physics Peking University  Beijing 100871 China"},{"name":"Peking\u2010Tsinghua Joint Center for Life Sciences Peking University  Beijing 100871 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuwen","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Artificial Microstructures and Mesoscopic Physics Laboratory of Electron Microscopy School of Physics Peking University  Beijing 100871 China"},{"name":"Peking\u2010Tsinghua Joint Center for Life Sciences Peking University  Beijing 100871 China"},{"name":"AI for Science (AI4S)\u2010Preferred Program School of Chemical Biology and Biotechnology Peking University  Shenzhen 518055 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaolong","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Artificial Microstructures and Mesoscopic Physics Laboratory of Electron Microscopy School of Physics Peking University  Beijing 100871 China"},{"name":"Peking\u2010Tsinghua Joint Center for Life Sciences Peking University  Beijing 100871 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Artificial Microstructures and Mesoscopic Physics Laboratory of Electron Microscopy School of Physics Peking University  Beijing 100871 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aidan A.","family":"Kendra","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Molecular Sciences Johns Hopkins School of Medicine  Baltimore MD 21205 USA"},{"name":"The SJ Yan and HJ Mao Laboratory of Chemical Biology Johns Hopkins School of Medicine  Baltimore MD 21205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth S.","family":"Margolis","sequence":"additional","affiliation":[{"name":"Solomon H. 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