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Here we introduce a drug discovery framework that exploits high-throughput proteomics to map and mitigate toxicity mechanisms of emerging drug modalities. Exposing androgen receptor (AR)-negative cells to a library of experimental AR-HBDs indicated for treatment-resistant prostate cancer linked widespread proteomic responses to hepatotoxicity of phthalimide degraders. Machine learning trained on proteomes mapped the primary toxicity mechanism to inhibition of electron transport chain complex I and identified safer analogs where a minor modification in the linker region mitigated off-target engagement. Proteome-optimized degraders displayed decreased hepatotoxicity, enhanced specificity and antitumor activity against treatment-resistant prostate cancer xenografts. Our findings establish a versatile framework for developing safer medicines and highlight the transformative potential of proteome-guided drug discovery.<\/jats:p>","DOI":"10.1038\/s41589-026-02347-2","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T09:02:15Z","timestamp":1791536535000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proteome-guided drug discovery maps and mitigates therapeutic degrader toxicity"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2648-4827","authenticated-orcid":false,"given":"Shaon","family":"Basu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5203-3603","authenticated-orcid":false,"given":"Jason Shu Lim","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Bosak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharan K.","family":"Bagal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6566-0868","authenticated-orcid":false,"given":"Claire","family":"Crafter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5964-1465","authenticated-orcid":false,"given":"Charlene","family":"Fallan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Lemke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Freiwald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0923-974X","authenticated-orcid":false,"given":"Matthew E. 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