Hydroxysteroid Dehydrogenase (17β -HSD3, 17β-HSD5, and 3α-HSD3) Inhibitors:Extragonadal Regulation of Intracellular Sex Steroid Hormone Levels
Michael L. Mohler, Ramesh Narayanan, Yali He, Duane D. Miller and James T. Dalton
Affiliation: GTx, Inc., 3 North Dunlap Street, Memphis, TN 38163, USA.
Keywords: 17β-HSD, 3α-HSD, androgen-dependent diseases, prostate cancer, steroid biosynthesis, enzyme inhibitors, 17β-HSD3, 3α-HSD3 (also known as: AKR1C2), 17β-HSD5 (also known as: AKR1C3, 3α-HSD2
Sex hormone signaling regulates the growth, differentiation and development of many tissues. The intracellular concentrations of sex hormones are regulated by several enzymes, including the 17β-hydroxysteroid dehydrogenases (17β-HSDs) and 3α- hydroxysteroid dehydrogenases (3α-HSDs). Most notably, these enzymes are involved in the oxidation and reduction of ketone and β- hydroxyl groups at the C17 position of androgens and estrogens. Fourteen mammalian 17β-HSDs have been identified to date; and are grouped into oxidative enzymes (17β-HSD types 2, 4, 6, 8, 9, 10, 11 and 14) that catalyze the NAD+-dependent inactivation of sex hormones and reductive enzymes (17β-HSD types 1, 3, 5 and 7) that catalyze the formation of more potent steroid receptor ligands. The proliferative effects of androgens and estrogens in target tissues and over-expression of 17β-HSDs in cancer have led to intense drug discovery efforts to identify and develop 17β-HSD inhibitors that can be used for the treatment of breast, prostate and endometrial cancers, neurological disorders, endometriosis, acne, hirsutism and other hormone dependent and independent diseases. Potent and selective inhibitors of intracellular androgen biosynthesis have been reported and, recent proof-of-concept data suggests that these agents have utility in the treatment of androgen-dependent diseases. This review summarizes recent patents and scientific literature regarding steroidal and nonsteroidal 17β-HSD3, 17β-HSD5, and 3α-HSD3 inhibitors and their promise for treatment of androgen-dependent diseases.
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