Strategies to Inhibit Steroid Cytochrome P450 Enzymes to Benefit Human Health: Development of Steroid Ligands for P450s 17A1, 19A1, and 8B1 to Treat Cancer and Obesity

Abstract

Several human cytochrome P450 enzymes (P450s) found in steroid/oxysterol biosynthesis are therapeutic targets to treat disease. This review article describes current research strategies to develop various inhibitors of three steroid P450s (P450s 17A1, 19A1, and 8B1) in order to benefit human health. (i) P450 17A1 (17α-hydroxylase/17,20-lyase) activity involves the hydroxylation at C17 and cleavage of the 17-20 bond to yield androgens. Abiraterone and galeterone are steroid inhibitors of P450 17A1, which both bear heterocycles (pyridine and benzimidazole) at C17 of the steroid moiety, the location of the enzymatic activity of P450 17A1. (ii) P450 19A1, the enzyme also known as aromatase, catalyzes the cleavage of the C10-C19 bond of androgens to give estrogens. Exemestane, which has the steroid structure of an androgen possessing an exocyclic methylene at C6, is a successful inhibitor of P450 19A1 used to treat breast cancer. (iii) P450 8B1 is the oxysterol-12α-hydroxylase enzyme that catalyzes the hydroxylation of the C12 position of its steroid based substrates. The hydroxylation of the C12 position ultimately forms the bile acid, cholic acid, which has implications in obesity. Mouse lacking the gene for the expression of P450 8B1 resist weight gain and the inhibition of P450 8B1 activity has been suggested as a potential treatment of obesity. Studies towards a rationally designed inhibitor of P450 8B1 are described. This research in medicinal chemistry combines expertise in both organic synthesis and biochemistry, with the goal to improve human health.