PT  - JOURNAL ARTICLE
AU  - Dinesh Puppala
AU  - Hyosung Lee
AU  - Kyung Bo Kim
AU  - Hollie I. Swanson
TI  - Development of an Aryl Hydrocarbon Receptor Antagonist Using the Proteolysis-Targeting Chimeric Molecules Approach: A Potential Tool for Chemoprevention
AID  - 10.1124/mol.107.040840
DP  - 2008 Apr 01
TA  - Molecular Pharmacology
PG  - 1064--1071
VI  - 73
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/73/4/1064.short
4100  - http://molpharm.aspetjournals.org/content/73/4/1064.full
SO  - Mol Pharmacol2008 Apr 01; 73
AB  - Activation of the aryl hydrocarbon receptor (AHR) by agonists and environmental contaminants like dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) leads to many adverse biological effects, including tumor promotion. With this in mind, we propose that agents that block the AHR pathway may be therapeutically beneficial, particularly by exhibiting chemopreventive activities. In our current research, we have focused on the development of an AHR antagonist using a chemical genetic approach called PROTACS (PROteolysis-TArgeting Chimeric moleculeS). PROTACS is a novel approach of tagging small recognition sequences of a specific E3 ubiquitin ligase complex to a known ligand for the receptor of interest (AHR) for targeting its degradation. Here, we present the design and initial characterization of AHR targeting PROTACS (Apigenin-Protac) designed to degrade and inhibit the AHR in epithelial cells. Our results demonstrate the “proof of concept” of this approach in effectively blocking AHR activity in cultured cells. The American Society for Pharmacology and Experimental Therapeutics