PT - JOURNAL ARTICLE AU - Auvin, Serge AU - Öztürk, Harun AU - Abaci, Yusuf T AU - Mautino, Gisele AU - Meyer-Losic, Florence AU - Jollivet, Florence AU - Bashir, Tarig AU - de Thé, Hugues AU - Sahin, Umut TI - A molecule inducing androgen receptor degradation and selectively targeting prostate cancer cells AID - 10.26508/lsa.201800213 DP - 2019 Aug 01 TA - Life Science Alliance PG - e201800213 VI - 2 IP - 4 4099 - http://www.life-science-alliance.org/content/2/4/e201800213.short 4100 - http://www.life-science-alliance.org/content/2/4/e201800213.full SO - Life Sci. Alliance2019 Aug 01; 2 AB - Aberrant androgen signaling drives prostate cancer and is targeted by drugs that diminish androgen production or impede androgen–androgen receptor (AR) interaction. Clinical resistance arises from AR overexpression or ligand-independent constitutive activation, suggesting that complete AR elimination could be a novel therapeutic strategy in prostate cancers. IRC117539 is a new molecule that targets AR for proteasomal degradation. Exposure to IRC117539 promotes AR sumoylation and ubiquitination, reminiscent of therapy-induced PML/RARA degradation in acute promyelocytic leukemia. Critically, ex vivo, IRC117539-mediated AR degradation induces prostate cancer cell viability loss by inhibiting AR signaling, even in androgen-insensitive cells. This approach may be beneficial for castration-resistant prostate cancer, which remains a clinical issue. In xenograft models, IRC117539 is as potent as enzalutamide in impeding growth, albeit less efficient than expected from ex vivo studies. Unexpectedly, IRC117539 also behaves as a weak proteasome inhibitor, likely explaining its suboptimal efficacy in vivo. Our studies highlight the feasibility of AR targeting for degradation and off-target effects’ importance in modulating drug activity in vivo.