Castration-resistant prostate cancer (CRPC) remains a significant clinical challenge due to the ability of tumor cells to undergo intratumoral androgen synthesis, a process catalyzed by the CYP17A1 enzyme. The only CYP17A1 inhibitor available in therapy, abiraterone acetate, faces significant limitations due to its steroidal structure, which causes off-target effects and generates agonistic metabolites that paradoxically stimulate the androgen receptor (AR). This study presents the development of the D2AAK1M series, a novel class of non-steroidal potential CYP17A1 inhibitors based on a pyridine–piperidine scaffold. Through biomimetic design and molecular docking, we demonstrated that these compounds have the potential to coordinate the heme iron while achieving high shape complementarity within the catalytic pocket. In silico ADME profiling indicated superior physicochemical properties compared to abiraterone, including optimal lipophilicity, enhanced water solubility, and the potential to penetrate the blood–brain barrier for targeting CNS metastases. In vitro assay results correlated with a suggested mechanism, showing preferential cytotoxicity toward androgen-dependent LNCaP cells (AR+) while sparing AR-negative lines (DU145, PC3) and healthy human fibroblasts (BJ). Our compounds present a promising starting point for further development of non-steroidal CYP17A1 inhibitors.
Jastrzębski et al. (Wed,) studied this question.