Estradiol and estrone C-16 derivatives as inhibitors of type 1 17β-hydroxysteroid dehydrogenase: Blocking of ER+ breast cancer cell proliferation induced by estrone

Laplante, Yannick; Cadot, Christine; Fournier, Michelle-Audrey; Poirier, Donald

doi:10.1016/j.bmc.2007.11.007

Cited by 67 publications

(68 citation statements)

References 37 publications

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“…In fact, the C6b-alkylamide-E 2 (12) gave a better inhibition with 46% at 1 mM whereas the C6b-alkylamide-E 1 (13) gave almost no inhibition with 23% at 1 mM. The same tendency was also observed for the 16b-m-carbamoylbenzyl derivative of E 2 , compounds 14 and 15, recently reported as inhibitors of 17b-HSD1 [53]. At a concentration of 0.1 mM, the C17b-hydroxy compound 14 inhibited 77% the transformation of E 1 into E 2 , but only 51% was obtained for the C17-ketone analogue (IC 50 ¼ 44 and 171 nM for 14 and 15, respectively).…”

Section: Discussionsupporting

confidence: 68%

Improved synthesis of EM-1745, preparation of its C17-ketone analogue and comparison of their inhibitory potency on 17β-hydroxysteroid dehydrogenase type 1

Bérubé

Poirier

2009

Journal of Enzyme Inhibition and Medicinal Chemistry

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Endocrine therapies are widely used for the treatment of estrogen-sensitive diseases. 17b-hydroxysteroid dehydrogenase type 1 (17b-HSD1) is involved in the last step of the biosynthesis of potent estrogen estradiol (E 2 ). This enzyme catalyzes the reduction of the C17-ketosteroid estrone (E 1 ) into the C17b-hydroxy steroid E 2 using the cofactor NAD(P)H. The X-ray analysis of E 2 /adenosine bisubstrate inhibitor EM-1745 proven that this compound interacts with both the substrate-and the cofactor-binding sites. However, E 1 is a better substrate of 17b-HSD1 than E 2 . Thus, in order to improve the inhibitory potency of EM-1745, the C17-ketone analogue was prepared. During this work, a new and more efficient method for synthesizing EM-1745 was developed using an esterification and a cross-metathesis as key steps. Contrary to what was expected, the C17-ketone analogue of EM-1745 is a less potent inhibitor (IC 50 ¼ 12 nM) than the C17-alcohol (IC 50 ¼ 4 nM) in homogenated HEK-293 cells overexpressing 17b-HSD1. Our results contribute to the knowledge of an unexpected observation: the C17-ketone steroidal inhibitors of 17b-HSD1 are less potent than their corresponding C17-alcohol derivatives.

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Section: Discussionsupporting

confidence: 68%

Improved synthesis of EM-1745, preparation of its C17-ketone analogue and comparison of their inhibitory potency on 17β-hydroxysteroid dehydrogenase type 1

Bérubé

Poirier

2009

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Several preclinical studies indicate that HSD17B1 inhibitors are indeed capable of modulating estrogen responses in vitro and in vivo. 16,18,[37][38][39] In the present study, we report that expression of human HSD17B1 in a transgenic mouse model (HSD17B1TG mice) 17 not only induces anovulation, but also estrogendependent endometrial hyperplasia. Moreover, we demonstrate that this endometrial phenotype can be reversed using novel HSD17B1 inhibitors.…”

mentioning

confidence: 89%

Novel Hydroxysteroid (17β) Dehydrogenase 1 Inhibitors Reverse Estrogen-Induced Endometrial Hyperplasia in Transgenic Mice

Saloniemi

Järvensivu

Koskimies³

et al. 2010

The American Journal of Pathology

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Local estrogen production plays a key role in proliferative endometrial disorders, such as endometrial hyperplasia and cancer. Hydroxysteroid (17␤) dehydrogenase 1 (HSD17B1) is an enzyme that catalyzes with high efficiency the conversion of weakly active estrone into highly potent estradiol. Here we report that female transgenic mice expressing human HSD17B1 invariably develop endometrial hyperplasia in adulthood. These mice also fail to ovulate and have enhanced peripheral conversion of estrone into estradiol in a variety of target tissues, including the uterus. As in humans, endometrial hyperplasia in HSD17B1 transgenic female mice was reversible on ovulation induction , which triggers a rise in circulating progesterone levels , and in response to exogenous progestins. Strikingly , a treatment with an HSD17B1 inhibitor failed to restore ovulation yet completely reversed the hyperplastic morphology of epithelial cells in the glandular compartment , although less so in the luminal epithelium. The data indicate that human HSD17B1 expression enhances endometrial estrogen production, and consequently, estrogen-dependent proliferation. Therefore, HSD17B1 is a promising new therapeutic target in the management of estrogen-dependent endometrial diseases.

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“…Expression of 17b-HSD1 is increased in breast tumors of postmenopausal women and the level of expression has prognostic significance (15,17,18). Inhibiting 17b-HSD1 activity could thus constitute a valuable way of reducing E2 level with the aim of shrinking breast tumors (19)(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

“…Our group has previously reported the synthesis of a number of E2 derivatives modified at position 16 (19,(24)(25)(26)(27)(28) for use as 17b-HSD1 inhibitors. In one of these studies, CC-156 (16b-(m-carbamoylbenzyl)-E2; Fig.…”

Section: Introductionmentioning

confidence: 99%

A New Nonestrogenic Steroidal Inhibitor of 17β-Hydroxysteroid Dehydrogenase Type I Blocks the Estrogen-Dependent Breast Cancer Tumor Growth Induced by Estrone

Ayán

Maltais

Roy

et al. 2012

Molecular Cancer Therapeutics

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Abstract17b-Hydroxysteroid dehydrogenase type 1 (17b-HSD1) converts estrone (E1) into estradiol (E2) and is expressed in many steroidogenic tissues and breast cancer cell lines. Because the potent estrogen E2 stimulates the growth and development of hormone-dependent diseases, inhibition of the final step of E2 synthesis is considered a promising strategy for the treatment of breast cancer. On the basis of our previous study identifying 16b-(m-carbamoylbenzyl)-E2 (CC-156) as a lead compound for the inhibition of 17b-HSD1, we conducted a number of structural modifications to reduce its undesired residual estrogenic activity. The steroid derivative PBRM [3-(2-bromoethyl)-16b-(m-carbamoylbenzyl)-17b-hydroxy-1,3,5(10)-estratriene] emerged as a potent inhibitor of 17b-HSD1 with an IC 50 value of 68 nmol/L for the transformation of E1 into E2. When tested in the estrogen-sensitive breast cancer cell line T-47D and in mice, PBRM showed no estrogenic activity in the range of concentrations tested. Furthermore, with the purpose of evaluating the bioavailability of PBRM and CC-156 injected subcutaneously (2.3 mg/kg), we measured their plasmatic concentrations as a function of time, calculated the area under the curve (AUC 0-12h ) and showed a significant improvement for PBRM (772 ng Ã h/mL) compared with CC-156 (445 ng Ã h/mL). We next tested the in vivo efficiency of PBRM on the T-47D xenograft tumor model in female ovariectomized athymic nude mice. After a treatment with PBRM, tumor sizes in mice stimulated with exogenous E1 were completely reduced at the control group level (without E1 treatment). As a conclusion, PBRM is a promising nonestrogenic inhibitor of 17b-HSD1 for the treatment of estrogen-dependent diseases such as breast cancer.

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Estradiol and estrone C-16 derivatives as inhibitors of type 1 17β-hydroxysteroid dehydrogenase: Blocking of ER+ breast cancer cell proliferation induced by estrone

Cited by 67 publications

References 37 publications

Improved synthesis of EM-1745, preparation of its C17-ketone analogue and comparison of their inhibitory potency on 17β-hydroxysteroid dehydrogenase type 1

Improved synthesis of EM-1745, preparation of its C17-ketone analogue and comparison of their inhibitory potency on 17β-hydroxysteroid dehydrogenase type 1

Novel Hydroxysteroid (17β) Dehydrogenase 1 Inhibitors Reverse Estrogen-Induced Endometrial Hyperplasia in Transgenic Mice

A New Nonestrogenic Steroidal Inhibitor of 17β-Hydroxysteroid Dehydrogenase Type I Blocks the Estrogen-Dependent Breast Cancer Tumor Growth Induced by Estrone

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