Design and Synthesis of Specific Inhibitors of CYP26 for Blocking Retinoic Acid Metabolism: A Safer Approach to Retinoid Therapy for Skin Disease
OBJECTIVE; We will advance our development of novel specific inhibitors of the retinoic acid (RA) metabolizing P450 enzymes, CYP26A1 and CYP26B1, to treat skin disorders - an approach that will have significant safety advantages over current retinoid therapies. These inhibitors will be used primarily to target cystic acne but will also be evaluated for their therapeutic potential in treating other skin disorders including actinic keratosis, rosacea, oral leukoplakia and skin cancer. SUMMARY The goal of this proposal is to assess the potential use of novel CYP26 selective inhibitors for the treatment of acne. In particular, we will investigate differences in activity between CYP26A1, CYP26B1 or pan-specific inhibitors. We have established a novel baculovirus-based assay that will facilitate the screening of large numbers of compounds. We will use data from this screening program to rationally design novel, highly selective CYP26 inhibitors. The incoming MITACS fellow will work at Snieckus Innovations for elaborating the design and synthesis of these compounds.