Showing papers on "Hydroxysteroid dehydrogenase published in 2008"
TL;DR: It is demonstrated that it is 17β‐HSD1 which is important for E2 production and report the inhibition of E1‐stimulated breast tumor growth by STX1040, a non‐oestrogenic selective inhibitor of 17 β‐ HSD1, using a novel murine model, suggesting that 17β-HSD 1 inhibitors such as STX 1040 may provide a novel treatment for hormone‐dependent breast cancer.
Abstract: Oestradiol (E2) stimulates the growth of hormone-dependent breast cancer. 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) catalyse the pre-receptor activation/inactivation of hormones and other substrates. 17beta-HSD1 converts oestrone (E1) to active E2, but it has recently been suggested that another 17beta-HSD, 17beta-HSD12, may be the major enzyme that catalyses this reaction in women. Here we demonstrate that it is 17beta-HSD1 which is important for E2 production and report the inhibition of E1-stimulated breast tumor growth by STX1040, a non-oestrogenic selective inhibitor of 17beta-HSD1, using a novel murine model. 17beta-HSD1 and 17beta-HSD12 mRNA and protein expression, and E2 production, were assayed in wild type breast cancer cell lines and in cells after siRNA and cDNA transfection. Although 17beta-HSD12 was highly expressed in breast cancer cell lines, only 17beta-HSD1 efficiently catalysed E2 formation. The effect of STX1040 on the proliferation of E1-stimulated T47D breast cancer cells was determined in vitro and in vivo. Cells inoculated into ovariectomised nude mice were stimulated using 0.05 or 0.1 microg E1 (s.c.) daily, and on day 35 the mice were dosed additionally with 20 mg/kg STX1040 s.c. daily for 28 days. STX1040 inhibited E1-stimulated proliferation of T47D cells in vitro and significantly decreased tumor volumes and plasma E2 levels in vivo. In conclusion, a model was developed to study the inhibition of the major oestrogenic 17beta-HSD, 17beta-HSD1, in breast cancer. Both E2 production and tumor growth were inhibited by STX1040, suggesting that 17beta-HSD1 inhibitors such as STX1040 may provide a novel treatment for hormone-dependent breast cancer.
116 citations
TL;DR: Compound 5 turned out to be a highly potent inhibitor of 17beta-HSD1 showing good selectivity, medium cell permeation, reasonable metabolic stability, and little inhibition of hepatic CYP enzymes.
Abstract: Human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the reduction of the weak estrogen estrone (E1) to the highly potent estradiol (E2). This reaction takes place in the target cell where the estrogenic effect is exerted via the estrogen receptor (ER). Estrogens, especially E2, are known to stimulate the proliferation of hormone-dependent diseases. 17β-HSD1 is overexpressed in many breast tumors. Thus, it is an attractive target for the treatment of these diseases. Ligand- and structure-based drug design led to the discovery of novel, selective, and potent inhibitors of 17β-HSD1. Phenyl-substituted bicyclic moieties were synthesized as mimics of the steroidal substrate. Computational methods were used to obtain insight into their interactions with the protein. Compound 5 turned out to be a highly potent inhibitor of 17β-HSD1 showing good selectivity (17β-HSD2, ERα and β), medium cell permeation, reasonable metabolic stability (rat hepatic microsomes), and little inhibition of hepatic CYP en...
88 citations
TL;DR: In this article, a review of 17β-hydroxysteroid dehydrogenase type 1 inhibitors is presented, which are divided into two separate groups according to their chemical structures.
Abstract: 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 17β-hydroxysteroid dehydrogenases catalyze either oxidation of hydroxyl groups or reduction of keto groups at steroid position C17. The thoroughly characterized 17β-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 17β-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 17β-hydroxysteroid dehydrogenase type 1 published and patented since the previous review of 17β-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 17β- hydroxysteroid dehydrogenase type 1 inhibitors. Their estrogenic/ proliferative activities and selectivities over other 17β-hydroxysteroid dehydrogenases that are involved in local regulation of estrogen action (types 2, 7 and 12) are also presented.
85 citations
TL;DR: It is demonstrated that using 17beta-HSD1 inhibitors is a valuable strategy for reducing the level of E2 and consequently its proliferative effect in T-47D ER+ breast cancer cells.
79 citations
TL;DR: The 1-phenyl compound 32 showed a very high inhibitory activity for 17beta-HSD1 (IC50 = 20 nM) and good selectivity and pharmacokinetic properties after peroral application and SAR studies revealed that the compounds most likely bind according to binding mode B to the active site, i.e., the 6- phenyl moiety mimicking the steroidal A-ring.
Abstract: 17β-Estradiol (E2) is implicated in the genesis and the development of estrogen-dependent diseases. Its concentration is mainly regulated by 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), which catalyzes the reduction of the weak estrogen estrone (E1) to the highly potent E2. This enzyme is thus an important target for the treatment of hormone-dependent diseases. Thirty-seven novel substituted 6-phenyl-2-naphthols were synthesized and evaluated for 17β-HSD1 inhibition, selectivity toward 17β-HSD2 and the estrogen receptors (ERs) α and β, and pharmacokinetic properties. SAR studies revealed that the compounds most likely bind according to binding mode B to the active site, i.e., the 6-phenyl moiety mimicking the steroidal A-ring. While substitution at the phenyl ring decreased activity, introduction of substituents at the naphthol moiety led to highly active compounds, especially in position 1. The 1-phenyl compound 32 showed a very high inhibitory activity for 17β-HSD1 (IC50 = 20 nM) and good selecti...
69 citations
TL;DR: 17beta-Hydroxysteroid dehydrogenase (17betaHSD) type 13 has an N-terminal sequence similar to that of 17 betaHSD type 11, and both sequences function as an endoplasmic reticulum and lipid droplet-targeting signal.
66 citations
TL;DR: H6PDH was found in a wide variety of tissues, with the greatest concentrations in the liver, kidney, and Leydig cells, and some neurons were clearly immunoreactive by immunohistochemistry.
Abstract: Intracellular concentrations of the glucocorticoids cortisol and corticosterone are modulated by the enzymes 11β-hydroxysteroid dehydrogenase (11β-HSD) 1 and 2. 11β-HSD1 is a reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent microsomal reductase that converts the inactive glucocorticoids cortisone and 11-dehydrocorticosterone to their active forms, cortisol and corticosterone. Hexose-6-phosphate dehydrogenase (H6PDH) is an enzyme that generates NADPH from oxidized NADP (NADP+) within the endoplasmic reticulum. In the absence of NADPH or H6PDH to regenerate NADPH, 11β-HSD1 acts as a dehydrogenase and inactivates glucocorticoids, as does 11β-HSD2. A monoclonal antibody against H6PDH was produced to study the possibility that 11β-HSD1 in the absence of H6PDH may be responsible for hydroxysteroid dehydrogenase activity in tissues that do not express significant amounts of 11β-HSD2. H6PDH and 11β-HSD1 expression was surveyed in a variety of rat tissues by real-time RT-PCR, Western blot analysis, and immunohistochemistry. H6PDH was found in a wide variety of tissues, with the greatest concentrations in the liver, kidney, and Leydig cells. Although the brain as a whole did not express significant amounts of H6PDH, some neurons were clearly immunoreactive by immunohistochemistry. H6PDH was amply expressed in most tissues examined in which 11β-HSD1 was also expressed, with the notable exception of the renal interstitial cells, in which dehydrogenase activity by 11β-HSD1 probably moderates activation of the glucocorticoid receptor because rat renal interstitial cells do not have significant amounts of mineralocorticoid receptors. This antibody against the H6PDH should prove useful for further studies of enzyme activity requiring NADPH generation within the endoplasmic reticulum.
65 citations
TL;DR: By ablating HSD17B7 function, this work has uncovered an important requirement for this enzyme during fetal development, and the major cause of fetal death appears to be due to the cholesterol synthetic activity of this enzyme.
Abstract: Our laboratory has previously cloned and purified a protein named PRAP (prolactin receptor-associated protein) that was shown to be a novel 17beta-hydroxysteroid dehydrogenase (HSD) enzyme with dual activity. This enzyme, renamed HSD17B7 or PRAP/17beta-HSD7, converts estrone to estradiol and is also involved in cholesterol biosynthesis. The major site of its expression is the corpus luteum of a great number of species including rodents and humans. To examine the functional significance of HSD17B7 in pregnancy, we generated a knockout mouse model with targeted deletions of exons 1-4 of this gene. We anticipated a mouse with a severe fertility defect due to its inability to regulate estrogen levels during pregnancy. The heterozygous mutant mice are normal in their development and gross anatomy. The females cycle normally, and both male and female are fertile with normal litter size. To our surprise, the breeding of heterozygous mice yielded no viable HSD17B7 null mice. However, we found HSD17B7 null embryo alive in utero on d 8.5 and d 9.5. By d 10.5, the fetuses grow and suffer from severe brain malformation and heart defect. Because the brain depends on in situ cholesterol biosynthesis for its development beginning at d 10, the major cause of fetal death appears to be due to the cholesterol synthetic activity of this enzyme. By ablating HSD17B7 function, we have uncovered, in vivo, an important requirement for this enzyme during fetal development.
58 citations
TL;DR: The pair of hydroxysteroid dehydrogenases that regulate ligand access to the AR in human prostate are identified and it is found that type 3 3alpha-HSD (aldo-keto reductase (AKR)1C2) catalyzes the NADPH dependent reduction of the potent androgen 5alpha-dihydrotestosterone (5alpha-DHT) to yield the inactive androgen 3 alpha-androstanediol (3 alpha-diol).
58 citations
TL;DR: Analysis of serial deletion and site-directed mutants of the HSD17B2 promoter fused to a reporter gene indicated that RA induction requires a cis-regulatory sequence that binds the specificity protein (SP) class of transcription factors.
Abstract: Context: The enzyme 17β-hydroxysteroid dehydrogenase type 2 (HSD17B2) exerts a local antiestrogenic effect by metabolizing biologically active estradiol to inactive estrone in endometrial epithelial cells. Retinoic acid (RA) induces HSD17B2 expression, but the underlying mechanism is not known. Objective: Our objective was to elucidate the molecular mechanisms responsible for HSD17B2 expression in human endometrial cells. Method: Human endometrial Ishikawa and RL95–2 cell lines were cultured in the presence or absence of RA to analyze endogenous HSD17B2 expression, transcription factor complex formation, and promoter activity. Results: RA induced HSD17B2 mRNA levels in a dose- and time-dependent manner in endometrial cells. The RA antagonist ANG11273 abolished RA-induced HSD17B2 expression. Small interfering RNA ablation of RA receptor (RAR)α or retinoid X receptor (RXR)α completely blocked RA-induced HSD17B2 gene expression. Analysis of serial deletion and site-directed mutants of the HSD17B2 promoter fu...
53 citations
TL;DR: Syntheses and biological evaluation of novel non-steroidal inhibitors designed to mimic the E1 template are reported using information from potent steroidal inhibitors.
TL;DR: High-throughput screening of a small-molecule compound library resulted in the identification of a series of arylsulfonylpiperazines that are potent and selective inhibitors of human 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD1).
TL;DR: Kinetic analyses of cofactor and substrate utilization as well as the inhibition kinetics of M187T and S124T and the wild-type enzymes suggest that the 16-fold higher-affinity inhibition of 3beta-HSD1 by trilostane may be related to the presence of Met187 in 3 beta- HSD1 and Thr187 in 4alpha,5alpha-epoxy-testosterone.
TL;DR: The design of a bisubstrate inhibitor of 17beta-HSD1, the estradiol/adenosine hybrid EM-1745, is reviewed and strategies for future designs of inhibitors are proposed.
Patent•
27 Mar 2008
TL;DR: In this article, a novel class of compounds of the general formula (I), their use in therapy, pharmaceutical compositions comprising the compounds, as well as their use for the manufacture of medicaments are described.
Abstract: A novel class of compounds of the general formula (I), their use in therapy, pharmaceutical compositions comprising the compounds, as well as their use in the manufacture of medicaments are described. The present compounds modulate the activity of 11β -hydroxysteroid dehydrogenase type 1 (11βHSD1) and are accordingly useful in the treatment of diseases in which such a modulation is beneficial, e.g. the metabolic syndrome.
TL;DR: The crystal structure of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1) in ternary complex with the coenzyme NADP (+) and the potent inhibitor 3,5-dichlorosalicylic acid and the important role of the nonconserved residues Leu54, His222, Leu306, and Leu308 in inhibitor binding and selectivity was determined by site-directed mutagenesis.
Abstract: The crystal structure of human 20α-hydroxysteroid dehydrogenase (AKR1C1) in ternary complex with the coenzyme NADP+ and the potent inhibitor 3,5-dichlorosalicylic acid was determined at a resolution of 1.8 A. The inhibitor is held in place by a network of hydrogen bonding interactions with the active site residues Tyr55, His117, and His222. The important role of the nonconserved residues Leu54, His222, Leu306, and Leu308 in inhibitor binding and selectivity was determined by site-directed mutagenesis.
TL;DR: Expression of the human Ke 6 gene, 17β-hydroxysteroid dehydrogenase type 8, in E. coli and the substrate specificity of the expressed protein were examined and the tissue distribution of mRNA expression was studied using real-time PCR.
Abstract: Expression of the human Ke 6 gene, 17β-hydroxysteroid dehydrogenase type 8, in E. coli and the substrate specificity of the expressed protein were examined. The tissue distribution of mRNA expression of the human Ke 6 gene was also studied using real-time PCR. Human Ke 6 gene was expressed as an enzymatically-active His-tag fusion protein, whose molecular weight was estimated to be 32.5 kDa by SDS-polyacrylamide gel electrophoresis. Expressed human Ke 6 gene effectively catalyzed the conversion of estradiol into estrone. Testosterone, 5α-dihydrotestosterone, and 5-androstene-3β,17β-diol were also catalyzed into the corresponding 17-ketosteroid at 2.4–5.9% that of estradiol oxidation. Furthermore, expressed enzyme catalyzed the reduction of estrone to estradiol, but the rate was a mere 2.3%. Human Ke 6 gene mRNA was expressed in the various tissues examined, such as brain, cerebellum, heart, lung, kidney, liver, small intestine, ovary, testis, adrenals, placenta, prostate, and stomach. Expression of human Ke 6 gene mRNA was especially abundant in prostate, placenta, and kidney. The levels in prostate and placenta were higher than that in kidney, where it is known to be expressed in large quantities.
TL;DR: The 11 β -hydroxysteroid dehydrogenase isozymes (11 β -HSDs) are microsomal enzymes catalyzing the interconversion of active glucocorticoids (GCs) and their 11-keto counterparts in specific tissues.
Abstract: Publisher Summary The 11 β -hydroxysteroid dehydrogenase isozymes (11 β -HSDs) are members of the short-chain dehydrogenase/reductase (SDR) family, a functionally heterogeneous protein family comprising the majority of known hydroxysteroid dehydrogenases The 11 β -HSDs are microsomal enzymes catalyzing the inter-conversion of active glucocorticoids (GCs) and their 11-keto counterparts in specific tissues The chapter discusses the enzymology of the SDR superfamily and 11 β -HSD1 The 11 β -HSDs are different from most members of the SDR family owing to the presence of one or more amino-terminal transmembrane domains Selective inhibitors of 11β-HSD1 have potential as treatments for a number of important diseases including type 2 diabetes, obesity, metabolic syndrome, inflammation, atherosclerosis, and central nervous system (CNS) disorders The chapter describes the biological assays needed to confirm the mechanism of action of a compound and to show that the required target is being inhibited These assays include in vitro assays, cell-based assays, and in vivo assays Certain compounds function as inhibitors of 11 β -HSD1 Many 11 β -HSD inhibitors have been identified from natural compounds and their synthetic analogues The chapter describes in vivo studies of selected 11 β -HSD1 inhibitors and clinical studies on 11 β -HSD1 inhibitors The outcome of current trials on a number of selective inhibitors of 11 β -HSD1 is eagerly awaited to assess the potential of this new field to treat disease areas of unmet medical needs
TL;DR: Models of the enzyme-inhibitor complexes suggest that Tyr118 and Phe311 are important residues for inhibitor recognition and orientation in the active site of AKR1C21.
TL;DR: No estrogenic-like effect was served in the estrogen-sensitive tissues of the ovariectomized mouse model for 2-MeO- 16� -bromopropyl-E2, and a series of 2-methoxy (MeO) deriva- tives synthesized as non-estrogenic inhibitors of 17-HSD1 are investigated.
Abstract: hydroxysteroid dehydrogenase type 1 (17�-HSD1) was chosen as a key steroidogenic target enzyme to reduce the formation of estradiol (E2), which is the most potent estrogen This article completes a previous study by synthesizing and testing 16� -methylene derivatives (Br, Cl and OH) of E2 in order to gen- erate new structure-activity relationships This study also investigates a series of 2-methoxy (MeO) deriva- tives synthesized as non-estrogenic inhibitors of 17�-HSD1 The 2-MeO-E2 derivatives (16� -CH2Br, 16� - CH2OH and 16� -(CH2)3Br) are all less potent inhibitors (IC50 = 591, 380 and 580 μM) than analogues without the 2-MeO group (IC50 = 120, 127 and 099 μM, respectively) for the reduction of estrone into E2 by 17�-HSD1 overexpressed in HEK-293 cells Except for one compound, these E2 derivatives have shown an estrogenic-like effect on estrogen-sensitive T-47D cells at 1 �M A cytotoxic effect was also obtained at higher concentrations for two compounds tested on T-47D cells However, no estrogenic-like effect was ob- served in the estrogen-sensitive tissues (uterus and vagina) of the ovariectomized mouse model for 2-MeO- 16� -bromopropyl-E2
12 Feb 2008
TL;DR: In this paper, the localization of 3 beta-hydroxysteroid dehydrogenase (3beta-HSD) activity in the wall of canine perianal sinus (PS) was determined.
Abstract: In this study, the localization of 3 beta-hydroxysteroid dehydrogenase (3beta-HSD) activity in the wall of canine perianal sinus (PS) was determined. The 3 beta-HSD activity was found out both in the cytoplasm of cells, situated in the propria and forming clusters adjacently to apocrine glands and in the cytoplasm of some epithelial cells in apocrine cells' glands. The results obtained about the 3 beta-HSD activity allowed us to propose a role of this enzyme in PS development and possibly, in tumourogenesis.