CYP17- and CYP11B-dependent steroid hydroxylases as drug development targets.
Steroid hormone biosynthesis is catalyzed by the action of a series of cytochrome P450 enzymes as well as reductases. Defects in steroid hydroxylating P450s are the cause of several severe defects such as the adrenogenital syndrome (AGS), corticosterone methyl oxidase (CMO) I or II deficiencies, or pseudohermaphroditism. In contrast, overproduction of steroid hormones can be involved in breast or prostate cancer, in hypertension, and heart fibrosis. Besides inhibiting the action of the steroid hormones on the level of steroid hormone receptors by using antihormones, which often is connected with severe side effects, more recently the steroid hydroxylases themselves turned out to be promising new targets for drug development. Since the 3-dimensional structures of steroid hydroxylases are not yet available, computer models of the corresponding CYPs may help to develop new inhibitors of these enzymes. During the past years, the necessary test systems have been developed and new compounds have been synthesized, which displayed selective and specific inhibition of CYP17, CYP11B2, and CYP11B1. With some of these potential new drugs, clinical trials are under way. It can be expected that in the near future some of these compounds will contribute to our arsenal of new and selective drugs.
Hakki
Tarek
T
Institute of Biochemistry, P.O. Box 151150, Saarland University, D-66041 Saarbrücken, Germany.
Bernhardt
Rita
R
D000818:Animals; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D013254:Steroid 17-alpha-Hydroxylase; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase