Exemestane, a new steroidal aromatase inhibitor of clinical relevance

Lombardi, Paolo

doi:10.1016/s0925-4439(02)00096-0

Cited by 72 publications

(52 citation statements)

References 48 publications

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“…However, in postmenopausal women the source of estrogen production is attributed to the aromatization of adrenal and ovarian androgens (ASD and TST) to estrogens (E1 and E2) via the enzyme aromatase in peripheral tissues. 41 These steroid hormones, apart from being essential in the female sexual development, also play a significant role in the growth and proliferation of hormone-dependent breast cancer. This is because the estrogens bind to the estrogen receptor (ER), which activates the transcription of its target genes, thereby stimulating proliferation of human mammary cells.…”

Section: Methodsmentioning

confidence: 99%

“…41,48 In recent times, the aromatase inhibition has been studied by means of different computational techniques, where several AIs have been tested. 10,43,51,[53][54][55][56][57] In this paper, we have focused in particular on the EXE compound (6-methylene-androsta-1,4-diene-3,17-dione) because of the resemblance it has with the natural substrate ASD (androst-4-ene-3,17-dione).…”

Section: Methodsmentioning

confidence: 99%

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Theoretical Study of the Mechanism of Exemestane Hydroxylation Catalyzed by Human Aromatase Enzyme

Viciano

Martí

2016

J. Phys. Chem. B

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Human aromatase (CYP19A1) aromatizes the androgens to form estrogens via a three-step oxidative process.The estrogens are necessary in humans, mainly in women, because of the role they play in the sexual and reproductive development. However, these also are involved in the development and growth of hormonedependent breast cancer. Therefore, inhibition of the enzyme aromatase, by means of drugs known as aromatase inhibitors, is the frontline therapy for these types of cancers. Exemestane is a suicidal third-generation inhibitor of aromatase, currently used in the breast cancer treatment. In this study, the hydroxylation of exemestane catalyzed by aromatase has been studied by means of hybrid QM/MM methods. The Free Energy Perturbation calculations provided a free energy of activation for the hydrogen abstraction step (rate-limiting step) of 17 kcal/mol. The results reveal that the hydroxylation of exemestane is not the inhibition stage suggesting a possible competitive mechanism between the inhibitor and the natural substrate androstenedione in the first catalytic subcycle of the enzyme. Furthermore, the analysis of the interaction energy for the substrate and the cofactor in the active site, shows that the role of the enzymatic environment during this reaction consists of a transition state stabilization by means of electrostatic effects.3

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Theoretical Study of the Mechanism of Exemestane Hydroxylation Catalyzed by Human Aromatase Enzyme

Viciano

Martí

2016

J. Phys. Chem. B

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“…SAIs and NSAIs inhibit the enzyme aromatase in different ways (Lombardi 2002). SAIs such as exemestane are analogs of the natural aromatase substrate androstenedione.…”

Section: Pharmacologymentioning

confidence: 99%

Aromatase inhibitors in the breast cancer clinic: focus on exemestane

Asten¹,

Neven²,

Lintermans³

et al. 2014

Endocrine-Related Cancer

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Breast cancer is the most prevalent type of cancer in women and responsible for significant female cancer-related mortality worldwide. In the Western world, over 80% of breast cancers are hormone-receptor positive for which endocrine therapy is administered. The main anti-estrogen treatments in use consist of selective estrogen-receptor modulators, such as tamoxifen, and third-generation aromatase inhibitors (AIs), such as exemestane, letrozole, and anastrozole. In this review, the focus will lie on exemestane, its clinical use, and its side-effect profile. Exemestane is the only third-generation steroidal AI. Its efficacy as a first-line treatment in metastatic breast cancer has been demonstrated. Therefore, exemestane could be considered a valid first-line therapeutic option, but it also can be used in second-line or further situations. Exemestane is mostly used as part of sequential adjuvant treatment following tamoxifen, but in this setting it is also active in monotherapy. Furthermore, this AI has been studied in the neoadjuvant setting as presurgical treatment, and even as chemoprevention in high-risk healthy postmenopausal women. It may reverse side effects of tamoxifen, such as endometrial changes and thromboembolic disease but may also cause some inconvenient side effects itself. Additionally, there is a lack of total crossresistance between exemestane and nonsteroidal AIs as far as their anti-tumoral efficacy is concerned; moreover the two classes of AIs display a nontotal overlapping toxicity profile. Taking together, exemestane can be considered as a useful treatment option at all stages of breast cancer.

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“…Type II or non-steroidal AIs, covalently bind to aromatase, resulting in irreversible inhibition. Non-steroidal AIs include anastrozole, vorozole, and letrozole [12,13] . Previous studies have demonstrated that AIs provide an increased survival benefit compared with other therapies and have acceptable toxicity profiles with decreased virginal bleeding and thromboembolism and increased rash, diarrhea and vomiting [14,15] .…”

Section: Introductionmentioning

confidence: 99%

“…Keywords: aromatase; breast cancer; imidazolyl quinoline; triptoquinone A; homogeneous time-resolved fluorescence assay; highthroughput screening; molecular docking; drug discovery Acta Pharmacologica Sinica (2014Sinica ( ) 35: 1082Sinica ( -1092 doi: 10.1038/aps.2014 [12,13] . Previous studies have demonstrated that AIs provide an increased survival benefit compared with other therapies and have acceptable toxicity profiles with decreased virginal bleeding and thromboembolism and increased rash, diarrhea and vomiting [14,15] .…”

mentioning

confidence: 99%

Discovery of novel aromatase inhibitors using a homogeneous time-resolved fluorescence assay

Lao

et al. 2014

Acta Pharmacol Sin

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Aim: aromatase is an important target for drugs to treat hormone-dependent diseases, including breast cancer. The aim of this study was to develop a homogeneous time-resolved fluorescence (HTRF) aromatase assay suitable for high-throughput screening (HTS). Methods: A 384-well aromatase HTRF assay was established, and used to screen about 7000 compounds from a compound library. Anti-proliferation activity of the hit was evaluated using alamarBlue(R) assay in a hormone-dependent breast cancer cell line T47D. Molecular docking was conducted to elucidate the binding mode of the hit using the Discovery Studio program. Results: The Z′ value and signal to background (S/B) ratio were 0.74 and 5.4, respectively. Among the 7000 compounds, 4 hits (XHN22, XHN26, XHN27 and triptoquinone A) were found to inhibit aromatase with IC 50 values of 1.60±0.07, 2.76±0.24, 0.81±0.08 and 45.8±11.3 μmol /L, respectively. The hits XHN22, XHN26 and XHN27 shared the same chemical scaffold of 4-imidazolyl quinoline. Moreover, the most potent hit XHN27 at 10 and 50 μmol/L inhibited the proliferation of T47D cells by 45.3% and 35.2%, respectively. The docking study revealed that XHN27 docked within the active site of aromatase and might form a hydrogen bond and had a π-cation interaction with amino acid residues of the protein.Conclusion: XHN27, an imidazolyl quinoline derivative of flavonoid, is a potent aromatase inhibitor with anti-proliferation activity against breast cancer in vitro. The established assay can be used in HTS for discovering novel aromatase inhibitor.Keywords: aromatase; breast cancer; imidazolyl quinoline; triptoquinone A; homogeneous time-resolved fluorescence assay; highthroughput screening; molecular docking; drug discovery Acta Pharmacologica Sinica (2014Sinica ( ) 35: 1082Sinica ( -1092 doi: 10.1038/aps.2014 [12,13] . Previous studies have demonstrated that AIs provide an increased survival benefit compared with other therapies and have acceptable toxicity profiles with decreased virginal bleeding and thromboembolism and increased rash, diarrhea and vomiting [14,15] . As AIs sometimes have more severe bone, brain and heart side effects, research for alternative compounds is necessary [15][16][17] .Natural products, extracted from traditional medicines and foods, may be helpful for discovering novel AIs that may selectively target aromatase in the breast and reduce systemic toxicity [18] . Among these compounds, flavonoids [19] are the most commonly investigated agents due to their prominent aromatase inhibitory activity and high breast selectivity [18] . Moreover, flavonoids may modulate the multi-step process of carcinogenesis through cellular and molecular mechanisms [19] . Biochanin A (BCA), isolated from red clover (Trifolium pretense), is a common isoflavone product that can inhibit aromatase activity and cell growth in MCF-7 cells [20] . Furthermore, cyp19a1 mRNA abundance was significantly reduced by BCA through promoter regulation in SK-BR-3 cells [20] .The classical tritiated water release assay [21,22] is ...

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Exemestane, a new steroidal aromatase inhibitor of clinical relevance

Cited by 72 publications

References 48 publications

Theoretical Study of the Mechanism of Exemestane Hydroxylation Catalyzed by Human Aromatase Enzyme

Theoretical Study of the Mechanism of Exemestane Hydroxylation Catalyzed by Human Aromatase Enzyme

Aromatase inhibitors in the breast cancer clinic: focus on exemestane

Discovery of novel aromatase inhibitors using a homogeneous time-resolved fluorescence assay

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