17β-Hydroxysteroid dehydrogenases (17β-HSDs) as therapeutic targets: Protein structures, functions, and recent progress in inhibitor development

Marchais‐Oberwinkler, Sandrine; Henn, Claudia; Möller, Gabriele; Klein, Tobias; Negri, Matthias; Oster, Alexander; Spadaro, Alessandro; Werth, Ruth; Wetzel, Marie; Xu, Kuiying; Frotscher, Martin; Hartmann, Rolf W.; Adamski, Jerzy

doi:10.1016/j.jsbmb.2010.12.013

Cited by 190 publications

(156 citation statements)

References 145 publications

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“…Up to now, 14 different subtypes of 17β‐HSD have been identified in mammals and most of them belong to the short‐chain dehydrogenase:reductase superfamily (SDR). They catalyse NAD(P)H/NAD(P) + ‐dependent reductions/oxidations at the C‐17 position of different steroids (Peltoketo et al ., 1999; Moeller and Adamski, 2006, 2009; Marchais‐Oberwinkler et al ., 2011). The majority of 17β‐HSD enzymes are able to catalyse, at least to some extent, reverse reactions under in vitro conditions.…”

Section: Introductionmentioning

confidence: 99%

Engineering Mycobacterium smegmatis for testosterone production

Fernández-Cabezón

Galán

2016

Microbial Biotechnology

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SummaryA new biotechnological process for the production of testosterone (TS) has been developed to turn the model strain Mycobacterium smegmatis suitable for TS production to compete with the current chemical synthesis procedures. We have cloned and overexpressed two genes encoding microbial 17β‐hydroxysteroid: NADP 17‐oxidoreductase, from the bacterium Comamonas testosteroni and from the fungus Cochliobolus lunatus. The host strains were M. smegmatis wild type and a genetic engineered androst‐4‐ene‐3,17‐dione (AD) producing mutant. The performances of the four recombinant bacterial strains have been tested both in growing and resting‐cell conditions using natural sterols and AD as substrates respectively. These strains were able to produce TS from sterols or AD with high yields. This work represents a proof of concept of the possibilities that offers this model bacterium for the production of pharmaceutical steroids using metabolic engineering approaches.

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Section: Introductionmentioning

confidence: 99%

Engineering Mycobacterium smegmatis for testosterone production

Fernández-Cabezón

Galán

2016

Microbial Biotechnology

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“…Structural formulae of the test compounds (1)(2)(3)(4)(5)(6) 51,52 . Our potential anticancer agents were designed on the hormonally inactive D-seco-and/or 13a-estrone core.…”

Section: B-hsd1 Inhibition and Antiproliferative Effectsmentioning

confidence: 99%

“…The evoked pre-receptorial antihormonal effect offers a suitable option for the therapy of estrogen-dependent diseases. 17b-HSD1 inhibitors may serve as interesting drug targets of anti-estrogen therapy 2,10 .…”

Section: Introductionmentioning

confidence: 99%

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Comparative investigation of thein vitroinhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17β-hydroxysteroid dehydrogenase type 1

Herman

Szabó

Bacsa

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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The inhibitory effects of 13-epimeric estrones, D-secooxime and D-secoalcohol estrone compounds on human placental 17b-hydroxysteroid dehydrogenase type 1 isozyme (17b-HSD1) were investigated. The transformation of estrone to 17b-estradiol was studied by an in vitro radiosubstrate incubation method. 13a-Estrone inhibited the enzyme activity effectively with an IC 50 value of 1.2 mM, which indicates that enzyme affinity is similar to that of the natural estrone substrate. The 13b derivatives and the compounds bearing a 3-hydroxy group generally exerted stronger inhibition than the 13a and 3-ether counterparts. The 3-hydroxy13b-D-secoalcohol and the 3-hydroxy-13a-D-secooxime displayed an outstanding cofactor dependence, i.e. more efficient inhibition in the presence of NADH than NADPH. The 3-hydroxy13b-D-secooxime has an IC 50 value of 0.070 mM and is one of the most effective 17b-HSD1 inhibitors reported to date in the literature.

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“…5α-reductase inhibitors. [17][18][19][20] Although a number of steroidal and nonsteroidal inhibitors of 17β-HSD1 [21][22][23] are described and there is experimental evidence for the effectiveness of 17β-HSD1 inhibition against human tumor cell lines in vitro and in animal models, there is no inhibitor under clinical evaluation. Moreover, no proof of principle study in an animal disease model has been conducted for the indication endometriosis, although this is a widespread disease for which no adequate medical treatment is available.…”

Section: Figurementioning

confidence: 99%

Towards the evaluation in an animal disease model: Fluorinated 17β-HSD1 inhibitors showing strong activity towards both the human and the rat enzyme

Abdelsamie

Bey²,

Gargano

et al. 2015

European Journal of Medicinal Chemistry

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CitationTowards the evaluation in an animal disease model: Fluorinated 17-HSD1 inhibitors showing strong activity towards both the human and the rat enzyme. Abstract 17β-Estradiol (E2), the most potent human estrogen, is known to be involved in the etiology of estrogen-dependent diseases (EDD) like breast cancer and endometriosis. 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyses the last step of E2 biosynthesis and is thus a promising target for the treatment of EDD. The previously described bicyclic substituted hydroxyphenyl methanones (BSHs) display high inhibitory potency towards human 17β-HSD1, but marginal activity towards rodent 17β-HSD1, precluding a proof of principle study in an animal endometriosis model. The aim of this work was to perform structural optimizations in the BSHs class to enhance inhibitory activity against rodent (mouse and rat) 17β-HSD1 while maintaining activity against the human enzyme. The introduction of fluorine atoms on the benzoyl moiety resulted in compounds with the desired properties. Molecular docking and homology modelling were applied to elucidate the binding mode and interspecies differences in activity. Compound 33 is the most potent inhibitor of both human and rat 17β-HSD1 up to date (IC 50 = 2 nM and 97 nM, respectively).Keywords: 17β-Hydroxysteroid dehydrogenase type 1, Interspecies differences, Estrogendependent diseases, Estrogen mimetics, Non-steroidal inhibitors

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17β-Hydroxysteroid dehydrogenases (17β-HSDs) as therapeutic targets: Protein structures, functions, and recent progress in inhibitor development

Cited by 190 publications

References 145 publications

Engineering Mycobacterium smegmatis for testosterone production

Engineering Mycobacterium smegmatis for testosterone production

Comparative investigation of thein vitroinhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17β-hydroxysteroid dehydrogenase type 1

Towards the evaluation in an animal disease model: Fluorinated 17β-HSD1 inhibitors showing strong activity towards both the human and the rat enzyme

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