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

Abstract

Background: 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 identi ed AhR's role in the suppression of cancer cell growth. We hypothesized that that the AhR is a molecular target for therapeutic interventions, and that activation of the AhR by select AhR modulators in cancer cells could have anti-cancer properties including cell death. This study describes the discovery and characterization of a new class of anti-cancer agents targeting the AhR.Methods: We employed two independent small molecule screening approaches to identify novel modulators of the AhR with unique anti-cancer properties. We established the AhR selective effects of a highly selective modulator in cancer cells with or without the AhR expression and identi ed the mechanism of action of this anti-cancer compound.Results: We report the identi cation of CGS-15943, uniquely selective AhR modulator, that activates AhR signaling and induces apoptosis in an AhR-dependent manner in liver and breast cancer cell models.Investigation of the downstream signaling pathway of this newly identi ed modulator revealed novel upregulation of Fas-ligand, which is required for AhR-mediated apoptosis.Conclusions: We identi ed CGS-15943 as a novel AhR-selective modulator with anti-cancer properties using two parallel and distinct screening strategies. This compound induced AhR-dependent apoptosis in multiple mouse and human liver cancer cells. Our results provide a basis for the development of a new class of anti-cancer therapeutics targeting an underappreciated molecular target, the AhR.

Phenotypic Discovery of Triazolo[1,5-c]quinazolines as a First-In-Class Bone Morphogenetic Protein Amplifier Chemotype

“…None of these compounds mirrored the BMP phenotype of 1a in any of the assays, excluding adenosine-associated effectors as responsible targets. The same was true for the very recently reported activity of 1a on the aryl hydrocarbon receptor, which we could exclude as a BMP-relevant target compared to the selective AhR activator FICZ (Figure S6A–D).…”

The cyclin‐dependent kinase inhibitor p27Kip1 interacts with the aryl hydrocarbon receptor and negatively regulates its transcriptional activity

“…A long list of synthetic [1,[7][8][9][10][11][12][13], endogenous [14,15] and dietary molecules [16] have been identified that bind to AhR, in addition to ligands produced by commensal microbiota [17]. There is significant interest in developing AhR-targeted therapeutics for multiple diseases, particularly autoimmune disorders [18][19][20] and cancer [3,[8][9][10]21,22]. The feasibility of therapeutically targeting AhR is supported by the absence of overt toxicity in vivo when select highaffinity ligands are administered [11,19,20].…”

“…affinity and metabolic fate) and the biological context. A long list of synthetic [1,[7][8][9][10][11][12][13], endogenous [14,15] and dietary molecules [16] have been identified that bind to AhR, in addition to ligands produced by commensal microbiota [17]. There is significant interest in developing AhR-targeted therapeutics for multiple diseases, particularly autoimmune disorders [18][19][20] and cancer [3,[8][9][10]21,22].…”

AhR promotes phosphorylation of ARNT isoform 1 in human T cell malignancies as a switch for optimal AhR activity

“…Conversely, FICZ promotes the differentiation of inflammatory TH17 cells in certain contexts ( 28 , 69 ). AhR ligand-dependent conformational states leading to the recruitment of specific transcriptional coregulators and chromatin remodelers, or tissue-specific expression of coregulators, have been reported as mechanisms of AhR ligand-mediated immune cell polarization ( 70 – 75 ). Additionally, the concentration of AhR ligands within the microenvironment, and the subsequent duration of AhR activation, have been shown to elicit opposing T cell subsets ( 76 ).…”