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.
Subject(s)
20-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Enzyme Inhibitors/therapeutic use , 20-Hydroxysteroid Dehydrogenases/physiology , Amino Acid Sequence , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Catalytic Domain , Cinnamates/pharmacology , Drug Design , Drug Discovery , Flavonoids/pharmacology , Gonadal Steroid Hormones/metabolism , Humans , Models, Molecular , Neurotransmitter Agents/metabolism , Protein Structure, Secondary , Salicylates/pharmacology , Sequence AlignmentABSTRACT
Human hydroxysteroid dehydrogenase (HSD) AKR1C1 is a member of the aldo-keto reductase superfamily, and it functions mainly as a 20alpha-HSD. It catalyzes the reduction of the potent progesterone to the weak 20alpha-hydroxyprogesterone, and of 3alpha,5alpha-tetrahydroprogesterone (5alpha-THP; allopregnanolone) to 5alpha-pregnane-3alpha,20alpha-diol. AKR1C1 thus decreases the levels of progesterone and 5alpha-THP in peripheral tissue. Progesterone inhibits cell proliferation, stimulates differentiation of endometrial cells, and is also important for maintenance of pregnancy, while 5alpha-THP allosterically modulates the activity of the gamma-aminobutyric acid receptor. Inhibitors of AKR1C1 are thus potential agents for treatment of endometrial cancer and endometriosis, as well as other diseases like premenstrual syndrome, catamenial epilepsy and depressive disorders.We have synthesized a series of pyrimidine, phthalimido and athranilic acid derivatives, and have here examined their inhibitory properties towards AKR1C1. A common aldo-keto reductase substrate, 1-acenaphthenol, was used to monitor the NAD(+)-dependent oxidation catalyzed by AKR1C1. The most potent inhibitors of AKR1C1 were the pyrimidine derivative N-benzyl-2-(2-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-4-yl)acetamide (K(i)=17 microM) and the anthranilic acid derivative 2-(((2',3-dichlorobiphenyl-4-yl)carbonyl)(methyl)amino)benzoic acid (K(i)=33 microM), both of which are non-competitive inhibitors.
Subject(s)
20-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Phthalimides/pharmacology , Pyrimidines/pharmacology , ortho-Aminobenzoates/pharmacology , 20-Hydroxysteroid Dehydrogenases/metabolism , Humans , Kinetics , Magnetic Resonance Spectroscopy , Models, Molecular , Pyrimidines/chemistry , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Spectrometry, Mass, Electrospray Ionization , Substrate Specificity , ortho-Aminobenzoates/chemistryABSTRACT
Carcinogenesis of hormone-related cancers involves hormone-stimulated cell proliferation, which increases the number of cell divisions and the opportunity for random genetic errors. In target tissues, steroid hormones are interconverted between their potent, high affinity forms for their respective receptors and their inactive, low affinity forms. One group of enzymes responsible for these interconversions are the hydroxysteroid dehydrogenases, which regulate ligand access to steroid receptors and thus act at a pre-receptor level. As part of this group, the 17beta-hydroxysteroid dehydrogenases catalyze either oxidation of hydroxyl groups or reduction of keto groups at steroid position C17. The thoroughly characterized 17beta-hydroxysteroid dehydrogenase type 1 activates the less active estrone to estradiol, a potent ligand for estrogen receptors. This isoform is expressed in gonads, where it affects circulating levels of estradiol, and in peripheral tissue, where it regulates ligand occupancy of estrogen receptors. Inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 are thus highly interesting potential therapeutic agents for the control of estrogen-dependent diseases such as endometriosis, as well as breast and ovarian cancers. Here, we present the review on the recent development of inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 published and patented since the previous review of 17beta-hydroxysteroid dehydrogenase inhibitors of Poirier (Curr. Med. Chem., 2003, 10, 453). These inhibitors are divided into two separate groups according to their chemical structures: steroidal and non-steroidal 17beta-hydroxysteroid dehydrogenase type 1 inhibitors. Their estrogenic/ proliferative activities and selectivities over other 17beta-hydroxysteroid dehydrogenases that are involved in local regulation of estrogen action (types 2, 7 and 12) are also presented.