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In this study, we developed a simple, high\u2010throughput drug repurposing screening platform to find radiosensitizers from compounds approved by the U.S. Food and Drug Administration. A library of 1134 compounds was systematically screened at two concentrations (0.2 and 2\u2009\u03bcM) using LNCaP cells stably expressing Metridia luciferase, allowing highly sensitive and quantitative assessment of cell viability through luciferase activity in culture supernatants. In the primary screening, 8 and 12 candidate radiosensitizers were identified at 0.2\u2009\u03bcM and 2\u2009\u03bcM, respectively. In the secondary screening, 19 compounds were evaluated at two radiation doses (4\u2009Gy and 6\u2009Gy) and six drug concentrations, identifying 5 radiation\u2010sensitizing candidate compounds. Through this stepwise screening approach, cladribine was identified as the most potent radiosensitizer. Cladribine increased radiation\u2010induced cytotoxicity in multiple prostate cancer cell lines (22Rv1, DU145, and PC3), with dose\u2010modifying factors of 1.46, 1.55, and 1.43, respectively, based on the radiation dose needed to achieve 90% cell death. Mechanistically, cladribine prevented the repair of radiation\u2010induced DNA double\u2010strand breaks, shown by increased \u03b3H2AX levels. Importantly, its radiosensitizing effect was further confirmed in\u00a0vivo using 22Rv1 and DU145 xenograft models. This study demonstrates that a luciferase\u2010based high\u2010throughput drug repurposing platform is useful for identifying clinically relevant radiosensitizers, revealing that cladribine is a promising candidate for further translational research in prostate cancer radiotherapy.<\/jats:p>","DOI":"10.1111\/cas.70326","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T06:38:11Z","timestamp":1768891091000},"page":"1136-1147","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Compound Library Screening Identified Cladribine as a Novel Radiosensitizer for Prostate Cancer"],"prefix":"10.1111","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2023-7211","authenticated-orcid":false,"given":"Toshiki","family":"Oka","sequence":"first","affiliation":[{"name":"Department of Urology The University of Osaka Graduate School of Medicine  Suita Osaka 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