LYA914 is a novel oral drug designed to treat advanced prostate cancer, specifically castration-resistant prostate cancer. It belongs to a cutting-edge class of therapeutics called PROteolysis TArgeting Chimeras, or PROTACs. Unlike earlier androgen receptor (AR) degraders that target the ligand-binding domain—often prone to mutations and splice variants, LYA914 targets the highly conserved DNA-binding domain of the AR. This allows it to degrade both full-length androgen receptors and resistant splice variants such as AR-V7, which frequently contribute to therapy resistance.

In pre-clinical studies, LYA914 inhibited the growth of prostate cancer cells, including cell lines resistant to enzalutamide, a commonly used drug. In animal models, oral LYA914 produced greater tumor growth inhibition compared to enzalutamide. According to research published in July 2025 in the Journal of Medicinal Chemistry, LYA914 works by tagging the AR protein, including its resistant forms, for destruction by the cell’s own protein disposal system.

PROTACs like LYA914 work by harnessing the body’s natural protein degradation machinery. They are bifunctional molecules with two key parts: one binds to the target protein (in this case, the androgen receptor), and the other recruits an E3 ubiquitin ligase enzyme. Bringing these two proteins together leads to the attachment of ubiquitin molecules to the target protein, marking it for degradation by the proteasome—a cellular “garbage disposal.” This process irreversibly removes the disease-causing protein rather than just inhibiting its activity, which can potentially overcome resistance mechanisms that affect other types of drugs.

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