2. Academic Validation
  3. Induction of Aryl Hydrocarbon Receptor-Mediated Cancer Cell-Selective Apoptosis in Triple-Negative Breast Cancer Cells by a High-Affinity Benzimidazoisoquinoline

Induction of Aryl Hydrocarbon Receptor-Mediated Cancer Cell-Selective Apoptosis in Triple-Negative Breast Cancer Cells by a High-Affinity Benzimidazoisoquinoline

  • ACS Pharmacol Transl Sci. 2023 Jun 7;6(7):1028-1042. doi: 10.1021/acsptsci.2c00253.
Daniel J Elson 1,  Bach D Nguyen 1,  Sebastian Bernales 2 3,  Sarvajit Chakravarty 2,  Hyo Sang Jang 1,  Nicholas A Korjeff 1,  Yi Zhang 1,  Sierra F Wilferd 4,  David J Castro 5 6,  Christopher L Plaisier 4,  Darren Finlay 5,  Robert G Oshima 5,  Siva K Kolluri 1 7 8
Affiliations

Affiliations

  • 1 Cancer Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon, 97331, United States.
  • 2 Praxis Biotech, San Francisco, California, 94158, United States.
  • 3 Centro Ciencia & Vida, Avda. Del Valle Norte 725, Santiago, 8580702, Chile.
  • 4 School of Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona 85287, United States.
  • 5 Sanford Burnham Prebys Medical Discovery Institute, NCI Designated Cancer Center, La Jolla, California, 92037, United States.
  • 6 Oregon Health & Science University, Portland, Oregon, 97239, United States.
  • 7 Linus Pauling Institute, Oregon State University, Corvallis, Oregon, 97331, United States.
  • 8 The Pacific Northwest Center for Translational Environmental Health Research, Oregon State University, Corvallis, Oregon, 97331, United States.
PMID: 37470014 DOI: 10.1021/acsptsci.2c00253
Abstract

Triple-negative breast Cancer (TNBC) remains a disease with a paucity of targeted treatment opportunities. The Aryl Hydrocarbon Receptor (AhR) is a ligand-activated transcription factor that is involved in a wide range of physiological processes, including the sensing of xenobiotics, immune function, development, and differentiation. Different small-molecule AhR ligands drive strikingly varied cellular and organismal responses. In certain cancers, AhR activation by select small molecules induces cell cycle arrest or Apoptosis via activation of tumor-suppressive transcriptional programs. AhR is expressed in triple-negative breast cancers, presenting a tractable therapeutic opportunity. Here, we identify a novel ligand of the Aryl Hydrocarbon Receptor that potently and selectively induces cell death in triple-negative breast Cancer cells and TNBC stem cells via the AhR. Importantly, we found that this compound, Analog 523, exhibits minimal cytotoxicity against multiple normal human primary cells. Analog 523 represents a high-affinity AhR ligand with potential for future clinical translation as an Anticancer agent.

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