Urolithin A analog inhibits castration-resistant prostate cancer by targeting the androgen receptor and its variant, androgen receptor-variant 7. Academic Article uri icon

abstract

  • We investigated the efficacy of a small molecule ASR-600, an analog of Urolithin A (Uro A), on blocking androgen receptor (AR) and its splice variant AR-variant 7 (AR-V7) signaling in castration-resistant prostate cancer (CRPC). ASR-600 effectively suppressed the growth of AR+ CRPC cells by inhibiting AR and AR-V7 expressions; no effect was seen in AR- CRPC and normal prostate epithelial cells. Biomolecular interaction assays revealed ASR-600 binds to the N-terminal domain of AR, which was further confirmed by immunoblot and subcellular localization studies. Molecular studies suggested that ASR-600 promotes the ubiquitination of AR and AR-V7 resulting in the inhibition of AR signaling. Microsomal and plasma stability studies suggest that ASR-600 is stable, and its oral administration inhibits tumor growth in CRPC xenografted castrated and non-castrated mice. In conclusion, our data suggest that ASR-600 enhances AR ubiquitination in both AR+ and AR-V7 CRPC cells and inhibits their growth in vitro and in vivo models.

published proceedings

  • Front Pharmacol

altmetric score

  • 1

author list (cited authors)

  • Chandrasekaran, B., Tyagi, A., Saran, U., Kolluru, V., Baby, B. V., Chirasani, V. R., ... Damodaran, C.

citation count

  • 0

complete list of authors

  • Chandrasekaran, Balaji||Tyagi, Ashish||Saran, Uttara||Kolluru, Venkatesh||Baby, Becca V||Chirasani, Venkat R||Dokholyan, Nikolay V||Lin, Jyh M||Singh, Amandeep||Sharma, Arun K||Ankem, Murali K||Damodaran, Chendil

publication date

  • January 2023