aceProteome-guided drug discovery maps and mitigates therapeutic degrader toxicity
Heterobifunctional targeted degraders (HBDs) enable potent removal of protein targets but their clinical success can be hindered by de novo toxicity inherent to their bivalent chemistry. 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…
Machine learning trained on proteomic responses traced degrader toxicity to complex I inhibition and guided a small linker change that reduced liver toxicity while keeping antitumor activity in mouse xenografts.
Heterobifunctional degraders for treatment-resistant prostate cancer showed hepatotoxicity linked to phthalimide degraders, a toxicity that can hinder their clinical success.
Evidence
- Peer-reviewedNature Chemical Biology2026-10-09
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Truvace Impact Record TRV-2026-1644, v1: “Proteome-guided drug discovery maps and mitigates therapeutic degrader toxicity.” Truvace, 2026-10-17. /record/TRV-2026-1644 (accessed at citation time). sha256 c7b7e277f05c7f8c…
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