Targeting the Aryl Hydrocarbon Receptor with Microbial Metabolite Mimics Alleviates Experimental Colitis in Mice

• Published in: Journal of medicinal chemistry 2022-05, Vol.65 (9), p.6859-6868
• Main Authors: Grycová, Aneta, Joo, Hansol, Maier, Vítězslav, Illés, Peter, Vyhlídalová, Barbora, Poulíková, Karolína, Sládeková, Lucia, Nádvorník, Petr, Vrzal, Radim, Zemánková, Lenka, Pečinková, Petra, Poruba, Martin, Zapletalová, Iveta, Večeřa, Rostislav, Anzenbacher, Pavel, Ehrmann, Jiří, Ondra, Peter, Jung, Jong-Wha, Mani, Sridhar, Dvořák, Zdeněk
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c00208

Targeting the aryl hydrocarbon receptor (AhR) is an emerging therapeutic strategy for multiple diseases (e.g., inflammatory bowel disease). Thermosporothrix hazakensis microbial metabolite 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is a putative AhR endogenous ligand. To improve the chemical stability, we synthesized a series of ITE chemical mimics. Using a series of in vitro assays, we identified 2-(1H-indole-3-carbonyl)-N-methyl thiazole-4-carboxamide (ITE-CONHCH3) as a highly potent (EC50 = 1.6 nM) AhR agonist with high affinity (K i = 88 nM). ITE-CONHCH3 triggered AhR nuclear translocation and dimerization of AhR-ARNT, enhanced AhR binding in the CYP1A1 promoter, and induced AhR-regulated genes in an AhR-dependent manner. The metabolic stability of ITE-CONHCH3 in a cell culture was 10 times higher than that of ITE. Finally, we observed protective effects of ITE-CONHCH3 in mice with DSS-induced colitis. Overall, we demonstrate and validate a concept of microbial metabolite mimicry in the therapeutic targeting of AhR.