Targeting ADAR1 with a Small Molecule for the Treatment of Prostate Cancer

Chemistry Medicinal Chemistry Urology Pharmacy Oncology Medicine
prostate cancer ADAR1 small molecule inhibitor tumor immunity RNA editing

Academic Background

Prostate cancer (PCA) is one of the most common malignancies in men, particularly in Western countries, where it is the second leading cause of cancer-related deaths among males. Although androgen signaling therapy is effective in the initial treatment of prostate cancer, most patients eventually relapse, and there is currently no curative treatment. Therefore, identifying new therapeutic targets and drugs has become a focal point of current research. The RNA-editing enzyme ADAR1 (Adenosine Deaminase Acting on RNA 1) has been found to promote cancer in various malignancies, but its specific function and potential therapeutic value in prostate cancer have not been fully explored. This study aims to reveal the critical role of ADAR1 in prostate cancer and develop an effective small-molecule inhibitor, providing a new strategy for prostate cancer treatment.

Source of the Paper

This paper was co-authored by Xiao Wang, Jiaxing Li, Yasheng Zhu, and others from multiple institutions, including China Pharmaceutical University, the University of Minnesota, and the University of Massachusetts. The paper was published in March 2025 in the journal Nature Cancer, titled “Targeting ADAR1 with a small molecule for the treatment of prostate cancer.”

Research Process

1. Expression and Function of ADAR1 in Prostate Cancer

The research team first analyzed the TCGA (The Cancer Genome Atlas) database and found that ADAR1 expression was significantly higher in prostate cancer tissues than in normal tissues. High ADAR1 expression was also associated with poor clinical prognosis. Through in vitro experiments, the team knocked down ADAR1 in three prostate cancer cell lines (DU-145, VCaP, and 22Rv1) and found that ADAR1 depletion significantly inhibited cancer cell proliferation, migration, and invasion, while inducing cell cycle arrest and apoptosis. Additionally, ADAR1 knockdown activated the interferon (IFN) signaling pathway, enhancing tumor immunogenicity.

2. Screening of RNA Editing Targets Regulated by ADAR1

To further explore the mechanism of ADAR1, the research team used RNA sequencing (RNA-seq) and RNA immunoprecipitation sequencing (RIP-seq) to identify RNA targets directly bound by ADAR1. The study found that ADAR1 regulates the translation of MTDH (Metadherin) by editing its 3’ untranslated region (3’ UTR), thereby promoting the proliferation and invasion of prostate cancer cells. MTDH is highly expressed in prostate cancer, and its expression level is positively correlated with ADAR1. Through a series of experiments, the team confirmed that ADAR1 maintains MTDH protein expression by inhibiting PKR (Protein Kinase R) activation and increasing MTDH RNA editing levels.

3. Development and Validation of the Small-Molecule Inhibitor ZYS-1

Based on the structure of ADAR1, the research team developed a novel small-molecule inhibitor, ZYS-1, through virtual screening and structural optimization. Experiments showed that ZYS-1 directly binds to ADAR1 and inhibits its deaminase activity, significantly suppressing prostate cancer cell proliferation, migration, and invasion, while inducing apoptosis. Additionally, ZYS-1 enhanced the tumor IFN signaling pathway, improving the efficacy of immunotherapy. In vivo experiments demonstrated that ZYS-1 significantly inhibited tumor growth and metastasis in prostate cancer mouse models without observable toxicity.

4. Broad-Spectrum Antitumor Effects of ZYS-1 in Multiple Cancers

The research team further tested the antitumor effects of ZYS-1 in various cancer cell lines and found that it exhibited significant antiproliferative activity against triple-negative breast cancer, liver cancer, gastric cancer, lung cancer, glioblastoma, and multiple myeloma, with IC50 values below 1 μM. Moreover, ZYS-1 showed promising inhibitory effects on primary acute myeloid leukemia (AML) cells, with IC50 values below 200 nM.

Research Findings

  1. High ADAR1 Expression in Prostate Cancer is Associated with Poor Prognosis: Analysis of the TCGA database and clinical samples confirmed that ADAR1 is highly expressed in prostate cancer, and its expression level is significantly correlated with tumor Gleason grade, high risk, and poor survival.

  2. ADAR1 Knockdown Inhibits Tumor Cell Proliferation and Activates IFN Signaling: In vitro experiments showed that ADAR1 knockdown significantly inhibited prostate cancer cell proliferation, migration, and invasion, while inducing cell cycle arrest and apoptosis. Additionally, ADAR1 knockdown activated the IFN signaling pathway, enhancing tumor immunogenicity.

  3. ADAR1 Regulates Prostate Cancer Cell Proliferation and Invasion by Editing MTDH: Using RNA-seq and RIP-seq, the research team identified RNA targets directly bound by ADAR1 and confirmed that ADAR1 regulates MTDH translation by editing its 3’ UTR, thereby promoting prostate cancer cell proliferation and invasion.

  4. ZYS-1 as an ADAR1 Inhibitor Significantly Suppresses Prostate Cancer Growth and Metastasis: ZYS-1 directly binds to ADAR1 and inhibits its deaminase activity, significantly suppressing prostate cancer cell proliferation, migration, and invasion, while inducing apoptosis. In vivo experiments demonstrated that ZYS-1 significantly inhibited tumor growth and metastasis in prostate cancer mouse models without observable toxicity.

  5. ZYS-1 Exhibits Broad-Spectrum Antitumor Effects in Multiple Cancers: ZYS-1 showed significant antiproliferative activity against triple-negative breast cancer, liver cancer, gastric cancer, lung cancer, glioblastoma, and multiple myeloma, with IC50 values below 1 μM. Additionally, ZYS-1 exhibited promising inhibitory effects on primary AML cells, with IC50 values below 200 nM.

Conclusions and Significance

This study is the first to systematically reveal the critical role of ADAR1 in prostate cancer and develop a novel small-molecule inhibitor, ZYS-1. ZYS-1 not only significantly inhibits prostate cancer growth and metastasis but also enhances the efficacy of tumor immunotherapy. Moreover, ZYS-1 exhibits broad-spectrum antitumor effects in multiple cancers, providing a new strategy for cancer treatment. The scientific value of this study lies in elucidating the molecular mechanism of ADAR1 in prostate cancer and providing important experimental evidence for the development of ADAR1-targeted anticancer drugs. Its application value lies in ZYS-1 as a novel anticancer drug with broad prospects, particularly in the treatment of prostate cancer and other malignancies.

Research Highlights

  1. Reveals the Critical Role of ADAR1 in Prostate Cancer: This study is the first to systematically reveal the high expression of ADAR1 in prostate cancer and its association with poor prognosis, while elucidating its molecular mechanism in regulating tumor cell proliferation and invasion through MTDH editing.

  2. Develops the Novel Small-Molecule Inhibitor ZYS-1: Through virtual screening and structural optimization, the research team successfully developed ZYS-1, which directly binds to ADAR1 and inhibits its deaminase activity, significantly suppressing prostate cancer growth and metastasis.

  3. ZYS-1 Exhibits Broad-Spectrum Antitumor Effects in Multiple Cancers: ZYS-1 not only shows significant antitumor effects in prostate cancer but also exhibits broad-spectrum activity in multiple other cancers, providing a new strategy for cancer treatment.

  4. Enhances the Efficacy of Tumor Immunotherapy: ZYS-1 activates the IFN signaling pathway, enhancing tumor immunogenicity and significantly improving the efficacy of immunotherapy.

Additional Valuable Information

This study also found that ZYS-1 exhibited good safety in in vivo experiments, with no observable toxicity. Additionally, ZYS-1 showed promising inhibitory effects on acute myeloid leukemia (AML) cells, providing new possibilities for AML treatment.