17ß-hydroxysteroid dehydrogenase inhibitors

Abstract

17ß-hydroxysteroid dehydrogenases (17ß-HSDs) are enzymes which require NAD(P)(H) for activity and are responsible for reduction or oxidation of hormones, fatty acids and bile acids in vivo, regulating the amount of the active form which is available to bind to its receptor. Fifteen 17b-HSDs have been identified to date, and with one exception, 17ß-HSD Type 5 (17ß-HSD5), an aldo-keto reductase, they are all short chain dehydrogenases/reductases. Although named as 17ß-HSDs, reflecting the major redox activity at the 17ß-position of the steroid, overall homology between the enzymes is low and the activities of these fifteen enzymes vary, with several of the 17ß-HSDs able to reduce and / or oxidise multiple substrates at various positions. These activities are involved in the progression of a number of diseases, including those related to steroid metabolism. Many groups are now working on inhibitors specific for several of these enzymes for the treatment of steroid-dependent diseases, including breast and prostate cancer, and endometriosis, with demonstrable efficacy in in vivo disease models, although none have yet reached clinical trials. In this review the recent advances in the development of specific inhibitors of the 17ß-HSD1, 3 and 5 enzymes as targets for the treatment of these diseases and the models used for their evaluation will be discussed.