Cancer Chemoprevention: Selective Inhibition of Cytochrome P450 2A13

Abstract

4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) is one of the most prevalent and carcinogenic compounds in tobacco. NNK is selectively activated by human cytochrome P450 2A13 (CYP2A13) to form two carcinogens that generate DNA adducts. CYP2A13 is found in the respiratory tract where NNK‐derived adducts can result in lung cancer. CYP2A13 is 93.5% identical to the hepatic cytochrome P450 2A6 (CYP2A6), which does not efficiently metabolize NNK but does metabolize other xenobiotic compounds. Thus a selective inhibitor of CYP2A13 could be used as a chemopreventative for tobacco users. High throughput screening was used to identify small molecule scaffolds that selectively bound CYP2A13 over CYP2A6. One such scaffold was benzylmorpholine. A small library of benzylmorpholine analogs was generated and has been evaluated for differential ligand binding (Kd) and inhibition of human cytochrome P450 2A enzymes. Examination of these results is revealing selective compounds that could be used for the reduction of lung cancer related to DNA damage in tobacco users.