Prostate cancer is the most common cancer of the male reproductive system and the fifth leading cause of death among male cancer patients worldwide [1], [2]. Moreover, the incidence of prostate cancer in China is also increasing year by year, which seriously affects the health and quality of life of elderly men in China [3], [4]. At present, the most common method for treating prostate cancer in the world is endocrine therapy. Studies have found that androgen and androgen receptor (AR) play a key role in the occurrence and development of prostate cancer [5], [6]. AR is responsible for regulating the expression of various genes and promoting the proliferation of cancer cells [7], [8], [9]. Overexpression and mutation of AR can also lead to drug resistance issues in prostate cancer treatment [10], [11]. In clinical, AR antagonists are used to affect the effects of testosterone and dihydrotestosterone on the receptor activation, thereby inhibit the proliferation of prostate cancer cell and promote apoptosis [12], [13]. However, the vast majority of such drugs developed resistance during treatment, eventually leading to metastatic castration-resistant prostate cancer (mCRPC) and incurable problems [14], [15]. Till today, the research on overcoming the problem of prostate cancer drug resistance continues to be important [16].

PROTACs are targeted protein degradation technologies that use small molecule compounds to regulate protein levels [17], [18], [19]. The working principle of PROTACs is to recruit a specific E3 ligase to be close to a specific target protein, so that the target protein will be polyubiquitized, and then be recognized by the proteasome and degraded into short peptides and amino acids (Fig. 1a) [20]. At present, breakthroughs have been made in drug development based on AR PROTAC [21], and about five AR-targeting PROTAC molecules are already in clinical trials (Table 1), among which, ARV-110 is currently in phase II clinical trials with the fastest progress (NCT03888612) [22], [23]. With the advantages of wide range of action, high activity, and good selectivity, it is expected that more PROTAC molecules will not only be used as a tool for basic biology research, but also enter into the clinic in the future to bring benefits to human health.

Hydrophobic tag-based protein degradations (HyT-PDs) are another promising strategy for targeted protein degradation, akin to the PROTACs approach (Fig. 1b). HyT-PDs comprise a ligand for the protein of interest (POI), a middle linker and a highly hydrophobic group, such as adamantane and diphenylmethyl. The ligand fragment attached to the hydrophobic tag binds specifically to POI. The exposed hydrophobic group of the ligand then binds to the hydrophobic site of the protein, causing misfolding of the protein. This misfolded protein will be subsequently degraded by the ubiquitin–proteasome pathway in vivo, with the assistance of chaperone [24], [25], [26], [27].

In this paper, we used AR non-steroidal antagonist analog RU59063 [28] as AR protein ligand, adamantane and diphenylmethane as the hydrophobic tag ligands respectively, and introduced some rigid backbones such as aromatic ring, piperidine, piperazine, alkynyl and pyridine into the intermediate linker to design the AR degraders. A total of 48 new bifunctional chimeric molecules were synthesized, and the preliminary activity evaluation and structure–activity relationship analysis of these compounds were carried out in AR high-expressing LNCaP cells.