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.