Identification of novel functional inhibitors of 17β-hydroxysteroid dehydrogenase type III (17β-HSD3)

Spires, Thomas E.; Fink, Brian E.; Kick, Ellen K.; You, Dan; Rizzo, Christopher; Takenaka, Ivone M.; Lawrence, R. Michael; Ruan, Zheming; Salvati, Mark; Vite, Gregory D.; Weinmann, Roberto; Attar, Ricardo M.; Gottardis, Marco M.; Lorenzi, Matthew V.

doi:10.1002/pros.20279

Cited by 21 publications

(12 citation statements)

References 35 publications

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“…5j), was used by Bristol Myers Squibb (BMS) to initiate a large-scale screening programme (Spires et al 2005). Inhibition of 17b-HSD3 activity in transfected cell microsomes was assayed using a 96-well format scintillation proximity assay (SPA) with a testosterone-specific antibody for higher throughput of compounds than the usual radiolabelled TLC-based assay (Luu-The et al 1995).…”

Section: Inhibitors Of 17b-hsd3mentioning

confidence: 99%

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

Day¹,

Tutill²,

Purohit³

et al. 2008

Endocrine Related Cancer

114

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Abstract17b-Hydroxysteroid dehydrogenases (17b-HSDs) are enzymes that are responsible for reduction or oxidation of hormones, fatty acids and bile acids in vivo, regulating the amount of the active form that is available to bind to its cognate receptor. All require NAD(P)(H) for activity. Fifteen 17b-HSDs have been identified to date, and with one exception, 17b-HSD type 5 (17b-HSD5), an aldo-keto reductase, they are all short-chain dehydrogenases/reductases, although overall homology between the enzymes is low. Although named as 17b-HSDs, reflecting the major redox activity at the 17b-position of the steroid, the activities of these 15 enzymes vary, with several of the 17b-HSDs able to reduce and/or oxidise multiple substrates at various positions. These activities are involved in the progression of a number of diseases, including those related to steroid metabolism. Despite the success of inhibitors of steroidogenic enzymes in the clinic, such as those of aromatase and steroid sulphatase, the development of inhibitors of 17b-HSDs is at a relatively early stage, as at present none have yet reached clinical trials. However, many groups are now working on inhibitors specific for several of these enzymes for the treatment of steroid-dependent diseases, including breast and prostate cancer, and endometriosis, with demonstrable efficacy in in vivo disease models. In this review, the recent advances in the validation of these enzymes as targets for the treatment of these diseases, with emphasis on 17b-HSD1, 3 and 5, the development of specific inhibitors, the models used for their evaluation, and their progress towards the clinic will be discussed.

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Section: Inhibitors Of 17b-hsd3mentioning

confidence: 99%

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

Day¹,

Tutill²,

Purohit³

et al. 2008

Endocrine Related Cancer

114

View full text Add to dashboard Cite

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“…Therefore, ligand-based models were developed for virtual screening. Multiple steroidal inhibitors were already reported [55,63]. However, more recently, a number of non-steroidal inhibitors have been published [49,64].…”

Section: Ligand-based Pharmacophore Modeling For 17ˇ-hsd3 Inhibitorsmentioning

confidence: 98%

“…For the second 17␤-HSD3 model, highly active, structurally diverse, non-steroidal, and preferably rigid compounds were [55] fulfilled these criteria (Fig. 2).…”

Section: Ligand-based Pharmacophore Modeling For 17ˇ-hsd3 Inhibitorsmentioning

confidence: 99%

Identification of chemically diverse, novel inhibitors of 17β-hydroxysteroid dehydrogenase type 3 and 5 by pharmacophore-based virtual screening

Schuster¹,

Kowalik

Kirchmair³

et al. 2011

The Journal of Steroid Biochemistry and Molecular Biology

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“…33 Many phytoestrogens (including flavonoids, coumarins, and coumestans) have been noted to inhibit 17-beta dehydrogenase. [34][35][36] 5 Alpha Reductase Inhibitors 5-alpha-reductase is the enzyme that is responsible for the conversion of testosterone into its active form, dihydrotestosterone (DHT). Since DHT has greater stimulatory and proliferative effects on the prostate gland compared to testosterone, prostate enlargement and cancer treatment may include inhibition of this enzyme.…”

Section: Sulfotransferasesmentioning

confidence: 99%

The Safety of Phytoestrogens in Menopause, Prostate and Breast Cancer

Stansbury¹,

Saunders²,

Winston³

2013

j restorat med

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Plant based natural products have been proposed as alternatives to the use of hormones for the treatment of menopausal symptoms, which has been associated with an increased risk of breast cancer and coronary artery disease. Specific herbal compounds such as Thai Kudzu root (Pueraria mirifica) have shown beneficial effects in the treatment of peri-menopausal symptoms and menopausal-related osteoporosis when used as an adjunct or as a single medicine. Pueraria mirifica has been used in conjunction with Vitex Berry (Vitex agnus-castus), Red Clover (Trifolium pratense) Sage (Salvia officinalis and S. miltiorrhiza), and Black Cohosh (Actaea racemosa), with the optional addition of natural progesterone and soy milk. Clinically, these compounds require careful dosing and are associated with variable times to efficacy. No known drug interactions exist, although research on the effects of phytoestrogens is limited. Phytoestrogens have not been associated with increased risk of cancer and therefore provide a safe alternative to standard treatment modalities.

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Identification of novel functional inhibitors of 17β-hydroxysteroid dehydrogenase type III (17β-HSD3)

Abstract: The identification of non-steroidal functional inhibitors of 17beta-HSD3 may be a useful complementary approach for the disruption of testosterone biosynthesis in the treatment of PCa.

Cited by 21 publications

References 35 publications

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

Identification of chemically diverse, novel inhibitors of 17β-hydroxysteroid dehydrogenase type 3 and 5 by pharmacophore-based virtual screening

The Safety of Phytoestrogens in Menopause, Prostate and Breast Cancer

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