Prostate cancer (PCa) is the most prevalent male cancer in the western world and the second most frequent malignancy in men worldwide [1,2]. The androgen/androgen receptor (AR) signaling pathway plays a central role in PCa development and progression, and PCa growth is usually androgen-dependent [[3], [4], [5]]. Androgen receptor (AR) antagonists (Fig. 1), such as enzalutamide (1) and apalutamide (2) which inhibit the AR signaling, are effective for the treatment of PCa [6,7]. Unfortunately, the development of castration-resistant prostate cancer (CRPC) becomes inevitable in a majority of the cases [8].

In the majority of tumors resistant to AR antagonists, AR is an important mediator of prostate cancer progression and considerable evidence exists to suggest that CRPC continues to depend on the AR signaling axis for continued cellular growth and survival [9]. Resistance is mainly driven by aberrations of the AR signaling pathway including AR gene amplification, AR gene mutations, and the expression of AR splice variants (e.g., AR variant 7; AR-V7) [10]. Considerable evidence demonstrates that truncated AR variants, particularly AR-V7, play vital roles in promoting CRPC progression during androgen deprivation therapy [11,12]. Additionally, clinical studies have shown patients with detectable AR-V7 expression had inferior prostate-specific antigen (PSA) responses as well as worse progression-free and overall survival compared with their AR-V7-negative counterparts [13]. Therefore, new therapeutic strategies to effectively target the AR signaling for metastatic castration-resistant PCa are urgently needed. It has been proposed that induced degradation of AR/AR-V7 protein could be potentially more effective in targeting the AR signaling than traditional AR antagonists [14]. Galeterone (5) was the first drug candidate evaluated in prostate cancer clinical trials that targets AR/AR-V7 degradation, AR/AR-V7 antagonism, and CYP17 inhibition. The Phase II trial of galeterone in CRPC demonstrated a PSA decline ≥30 % and ≥50 % in 83 % and 70 % of patients in the M0 and M1 TN cohorts, respectively. In the abiraterone-refractory cohort, among the 15 evaluable patients to date, 13 % achieved a PSA decline ≥30 % and 27 % had some degree of PSA decline (27,486,306). Galeterone will soon enter another Phase 3 clinical trials in prostate cancer. ARV-110 (6) discovered by scientists at Arvinas Inc. was the first-in-class potent and orally active AR-PROTAC degrader advanced into clinical development. In the phase 1 dose escalation study of ARV-110 in men with mCRPC who received ≥2 prior therapies (including abiraterone and/or enzalutamide), ARV-110 demonstrates clinical activity in a post-NHA with PSA50 rate of 40 % in patients with AR T878X/H875Y-positivetumors (n = 5) (NCT0388861). ARV-110 is currently in the phase 2 clinical trial in men with mCRPC (NCT05177042). Many new AR protac degraders (e.g. ARD-1676, BWA-522, ARD2051) are reported continuously. The above data for Galeterone and ARV-110 suggest that AR/AR-V7 degraders are promising new therapies for the treatment of mCRPC. As such, there is an urgent need to develop therapeutic strategies that effectively suppress the constitutive tumor-promoting signals associated with AR-FL and AR-V7 action in CRPC. In this study, we propose a pathway in next-generation anti-androgen resistance and prostate cancer progression: a) inhibiting AR function or nuclear translocation by binding to any or multiple domains of the AR and ARV7 protein; b) degrading the AR and ARV7 protein to prevent any inadvertent activation by any of the abovementioned alternate mechanisms.

Based on this information, we rationalize our profile of screening assays designed to overcome advanced PCs. We further designed and synthesized a series of small molecule AR antagonists, and reported that compound 20i is a promising novel AR antagonist with, a unique pharmacology and chemical structure that selectively binds, inhibits, and degrades the AR and AR-SVs, including AR-V7, at submicromolar concentrations. These results demonstrated that 20i prevented AR protein activation via reduction of the protein level of AR, providing a novel option for CRPC treatment.