Development of dual AR/ARV7 degraders with 3,5-dimethylisoxazole to overcome antiandrogen resistance in castration-resistant prostate cancer.

During the treatment of castration-resistant prostate cancer (CRPC) patients, the emergence of various resistance mechanisms compromises the efficacy of second-generation antiandrogens. Recently, the targeted protein degradation (TPD) strategy has been harnessed for the development of novel AR inhibitors, aiming to overcome current resistance mechanisms. Our previous studies identified Z15 as a selective androgen receptor degrader (SARD). Here, we optimized the structure of Z15 and identified ZA5 as a potent dual degrader of both AR and ARV7. ZA5 directly interacts with the ligand-binding domain (LBD) and the N-terminal domain (NTD) of AR, promoting the degradation of AR/ARV7. Moreover, ZA5 effectively suppresses the transcriptional activity of wild-type AR (AR-WT), AR mutants, and ARV7, while downregulating the mRNA and protein levels of downstream AR target genes, thereby overcoming antiandrogen resistance mediated by ARV7 and AR point mutations. This study provides a potential lead compound with dual AR/ARV7 inhibitory activity, offering a novel therapeutic strategy to combat drug resistance in CRPC.