Abstract LB133: An orally bioavailable degrader targeting androgen receptor and the splice variant in castration resistant prostate cancer

The development and progression of prostate cancer depends on androgen receptor (AR) whose sustained activity albeit the use of anti-androgen drugs accounts for one of the major mechanisms leading to drug resistance. As such, the clinical benefits of current therapeutic agents remain rather limited for the advanced prostate cancer. Given that expression of constitutively active AR variants (AR-Vs) that lack the ligand-binding domain (LBD) clinically associates with the drug resistance and poor survival, targeting both AR and the LBD-truncated AR-Vs is anticipated an effective approach to overcome therapy resistance. Here, we present Proteolysis Targeting Chimeras (PROTAC) compound ITRI-148, capable of effectively degrading both full-length and LBD-truncated AR by targeting the proteins via the N-terminal domain to Cereblon-mediated ubiquitination and degradation. Degradation of AR and AR-V7 suppresses target gene expression, and inhibits cell proliferation with accompanied apoptosis activation in AR-V7-expressing castration-resistant prostate cancer (CRPC) cell models. In vivo, this compound displays good pharmacokinetics profiles and oral bioavailability with strong antitumor efficacy towards castration-, enzalutamide-resistant CWR22Rv1 and VCaP xenograft models. These data provide compelling evidence that by targeting AR NTD for induced degradation of active AR protein variants, ITRI-148 is a promising agent for the intervention of advanced therapy-resistant prostate cancers.