Proteome-guided drug discovery maps and mitigates therapeutic degrader toxicity.

Proteome-guided drug discovery identified linker modifications that reduce hepatotoxicity and improve safety of androgen receptor-targeting degraders for prostate cancer.

• Why it matters: Heterobifunctional targeted degraders can cause de novo toxicity due to their bivalent chemistry, limiting their clinical use. Understanding and mitigating these toxicity mechanisms is crucial for safer drug development.
• What they did: Researchers used high-throughput proteomics and machine learning on prostate cancer cell models exposed to experimental AR-HBDs, mapping toxicity pathways and designing safer analogs with linker modifications.
• The result: Proteome-optimized degraders showed decreased hepatotoxicity, increased specificity, and improved antitumor activity, demonstrating a versatile framework for developing safer medicines.