Design, Synthesis, and Activity Evaluation of Novel Nucleosides as ADAR1 Inhibitor for the Treatment of Prostate Cancer

Prostate cancer (PCa) is a common malignant tumor in men, characterized by high incidence and mortality. Despite endocrine therapy being the primary treatment, drug resistance necessitates the exploration of new therapeutic agents. Nucleoside analogs, with their unique chemical structures and broad biological effects, have become essential in modern medicine. By modifying 2-chloroadenosine, we developed a series of compounds that inhibit prostate cancer. Notably, compound C12 significantly suppressed DU-145 cell proliferation (IC50 = 1.11 μM), clonogenicity, migration, and invasion, arrested cell cycle, and induced apoptosis. Importantly, transcriptome analysis, cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) confirmed ADAR1 as a potential target for C12. We also analyzed the binding mode of C12 to ADAR1. In vivo studies showed that C12 safely and effectively inhibited tumor growth in DU-145 and 22Rv1 xenograft models. In summary, C12 has been identified as a promising ADAR1 inhibitor for prostate cancer treatment.