title: Inhibitors of aldo-keto reductases AKR1C1-AKR1C4.
abstract: The AKR1C aldo-keto reductases (AKR1C1-AKR1C4) are enzymes that interconvert steroidal hormones between their active and inactive forms. In this manner, they can regulate the occupancy and trans-activation of the androgen, estrogen and progesterone receptors. The AKR1C isoforms also have important roles in the production and inactivation of neurosteroids and prostaglandins, and in the metabolism of xenobiotics. They thus represent important emerging drug targets for the development of agents for the treatment of hormone-dependent forms of cancer, like breast, prostate and endometrial cancers, and other diseases, like premenstrual syndrome, endometriosis, catamenial epilepsy and depressive disorders. We present here the physiological roles of these enzymes, along with their structural properties and an overview of the recent developments regarding their inhibitors. The most important strategies of inhibitor design are described, which include the screening of banks of natural compounds (like cinnamic acids, flavonoids, jasmonates, and related compounds), the screening of and structural modifications to non-steroidal anti-inflammatory drugs, the substrate-inspired design of steroidal and nonsteroidal inhibitors, and computer-assisted structure-based inhibitor design.
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia.
authors.forename: P
authors.initials: P
authors.lastname: Brožič
authors.forename: S
authors.initials: S
authors.lastname: Turk
authors.forename: T Lanišnik
authors.initials: TL
authors.lastname: Rižner
authors.forename: S
authors.initials: S
authors.lastname: Gobec
mesh_terms: D015089:20-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000502:physiology; D000595:Amino Acid Sequence; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry; D020134:Catalytic Domain; D002934:Cinnamates / Q000494:pharmacology; D015195:Drug Design; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005419:Flavonoids / Q000494:pharmacology; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D018377:Neurotransmitter Agents / Q000378:metabolism; D017433:Protein Structure, Secondary; D012459:Salicylates / Q000494:pharmacology; D016415:Sequence Alignment
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002934:Cinnamates; D004791:Enzyme Inhibitors; D005419:Flavonoids; D012739:Gonadal Steroid Hormones; D018377:Neurotransmitter Agents; D012459:Salicylates; D015089:20-Hydroxysteroid Dehydrogenases; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase