Received for publication August 13, 2007.
Revised January 3, 2008.
Accepted for publication January 3, 2008.

DEVELOPMENT OF AN AHR ANTAGONIST USING THE PROTACS APPROACH: A POTENTIAL TOOL FOR CHEMOPREVENTION

Abstract

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, it is proposed that agents that block the AHR pathway may be therapeutically beneficial in particular by exhibiting chemopreventive activities. In our current research we have focused on the development of an AHR antagonist using a chemical genetic approach called the PROTACS (PROteolysis TArgeting Chimeric moleculeS) approach. 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.

Key words: Ah receptor, Toxicant-induced gene express