2. Academic Validation
  3. Design, Synthesis, and Activity Evaluation of Novel Nucleosides as ADAR1 Inhibitor for the Treatment of Prostate Cancer

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

  • J Med Chem. 2025 Jul 24;68(14):14495-14513. doi: 10.1021/acs.jmedchem.5c00598.
Yasheng Zhu 1 2,  Hao Shen 1 2,  Jiayu Ding 1 2,  Minjie Wang 1 2,  Jiaying Ji 1 2,  Yi Hou 1 2,  Zeyu Cai 1 2,  Jiaxing Li 1 2,  Weijiao Chen 1 2,  Wenbin Kuang 1 2,  Liping Wang 1 2,  Wenjian Min 1 2,  Peng Yang 1 2 3,  Xiao Wang 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 3 Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China.
PMID: 40632646 DOI: 10.1021/acs.jmedchem.5c00598
Abstract

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.

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