Discovery and Mechanistic Characterization of a Select Modulator of AhR-regulated Transcription (SMAhRT) with Anti-cancer Effects

Edmond Francis O’Donnell, Hyo Sang Jang, Daniel F. Liefwalker, Nancy I. Kerkvliet, Siva Kumar Kolluri

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and a member of the bHLH/PAS (basic Helix-Loop-Helix/Per-Arnt-Sim) family of proteins. The AhR was cloned and characterized for its role in mediating the toxicity of dioxins. Subsequent research has identified the role of AhR in suppression of cancer cell growth. We hypothesized that the AhR is a molecular target for therapeutic intervention in cancer, and that activation of the AhR by unique AhR ligands in cancer cells could have anti-cancer effects including induction of cell death. This study describes the discovery and characterization of a new class of anti-cancer agents targeting the AhR, that we designate as Select Modulators of AhR-regulated Transcription (SMAhRTs). We employed two independent small molecule screening approaches to identify potential SMAhRTs. We report the identification of CGS-15943 that activates AhR signaling and induces apoptosis in an AhR-dependent manner in liver and breast cancer cells. Investigation of the downstream signaling pathway of this newly identified SMAhRT revealed upregulation of Fas-ligand (FasL), which is required for AhR-mediated apoptosis. Our results provide a basis for further development of a new class of anti-cancer therapeutics targeting an underappreciated molecular target, the AhR.

Original languageEnglish (US)
Pages (from-to)307-322
Number of pages16
Issue number5-6
StatePublished - Jun 2021


  • AhR
  • AhR-targeted cancer therapeutics
  • Anti-cancer therapeutics
  • Apoptosis
  • Arnt
  • Aryl hydrocarbon Receptor
  • Bax
  • Breast cancer
  • CGS-15943
  • CGS15943
  • Caspase
  • Fas ligand
  • FasL
  • Hepatocellular carcinoma
  • Hepatoma
  • Liver cancer
  • MRS1220
  • Nuclear receptor
  • SMAhRT
  • Select modulators
  • Small molecule screening
  • Targeted therapeutics
  • bHLH/PAS

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Cancer Research


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