Aromatase inhibitors: synthesis, biological activity, and binding mode of azole-type compounds

Furet, Pascal; Batzl, C.; Bhatnagar, Ajay S.; Francotte, Eric; Rihs, G.; Lang, Maria Chiara Dasso

doi:10.1021/jm00062a012

Cited by 100 publications

(72 citation statements)

References 15 publications

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“…6C and D). From a pharmacophore model (17), it can be concluded that PTK/ZK presents two structural characteristics consistent with its ability to inhibit aromatase: a heme-binding group and a hydrophobic moiety fitting in the sterically allowed region of the active site (Fig. 6C).…”

Section: Ptk/zk Has Antiproliferative Effects On Mcf7 Arom Cellsmentioning

confidence: 87%

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The Vascular Endothelial Growth Factor Receptor Inhibitor PTK787/ZK222584 Inhibits Aromatase

et al. 2009

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Endocrine therapy is well established for the treatment of breast cancer, and antiangiogenic agents are showing considerable promise. Targeting the vascular endothelial growth factor (VEGF) and estrogen receptor (ER) signaling pathways concomitantly may provide enhanced therapeutic benefit in ER-positive breast cancer. Therefore, the effects of the VEGF receptor (VEGFR) tyrosine kinase inhibitor PTK787/ZK222584 (PTK/ZK) were investigated using human breast cancer cell lines engineered to express aromatase. As expected in this system, estrogen (E2) or androstenedione induced a proliferative response and increased ER-mediated transcription in ER-positive cell lines expressing aromatase. However, surprisingly, in the presence of androstenedione, PTK/ZK suppressed both the androstenedione-stimulated proliferation and ERmediated transcription. PTK/ZK alone and in the presence of E2 had no observable effect on proliferation or ER-mediated transcription. These effects result from PTK/ZK having previously unrecognized antiaromatase activity and PTK/ZK being a competitive aromatase inhibitor. Computer-assisted molecular modeling showed that PTK/ZK could potentially bind directly to aromatase. The demonstration that PTK/ZK inhibits aromatase and VEGFR indicates that agents crossinhibiting two important classes of targets in breast cancer could be developed. [Cancer Res 2009;69(11):4716-23]

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Section: Ptk/zk Has Antiproliferative Effects On Mcf7 Arom Cellsmentioning

confidence: 87%

“…The pharmacophore model for aromatase inhibition is previously described (17). In the pharmacophore model, the most potent azole and steroid inhibitors of aromatase are aligned using the heme group of the enzyme as the reference anchoring point.…”

Section: Methodsmentioning

confidence: 99%

The Vascular Endothelial Growth Factor Receptor Inhibitor PTK787/ZK222584 Inhibits Aromatase

et al. 2009

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“…The third-generation AI letrozole (Femara 1 ) was the result of this structure-activity approach to drug design and achieved the research goal of creating a highly potent and totally selective AI [71]. These compounds were also used to design pioneering molecular modeling techniques used to map the active site of aromatase [70,72]. Other thirdgeneration AIs developed during this period were the nonsteroidal agents vorozole (since discontinued) and anastrozole [73] (Fig.…”

Section: Aromatase Inhibitorsmentioning

confidence: 99%

The discovery and mechanism of action of letrozole

Bhatnagar

2007

Breast Cancer Res Treat

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Because estrogen contributes to the promotion and progression of breast cancer, a greater understanding of the role of estrogen in breast cancer has led to therapeutic strategies targeting estrogen synthesis, the estrogen receptor, and intracellular signaling pathways. The enzyme aromatase catalyses the final step in estrogen biosynthesis and was identified as an attractive target for selective inhibition. Modern third-generation aromatase inhibitors (AIs) effectively block the production of estrogen without exerting effects on other steroidogenic pathways. The discovery of letrozole (Femara 1 ) achieved the goal of discovering a highly potent and totally selective AI. Letrozole has greater potency than other AIs, including anastrozole, exemestane, formestane, and aminoglutethimide. Moreover, letrozole produces near complete inhibition of aromatase in peripheral tissues and is associated with greater suppression of estrogen than is achieved with other AIs. The potent anti-tumor effects of letrozole were demonstrated in several animal models. Studies with MCF-7Ca xenografts successfully predicted that letrozole would be clinically superior to the previous gold standard tamoxifen and also indicated that it may be more effective than other AIs. An extensive program of randomized clinical trials has demonstrated the clinical benefits of letrozole across the spectrum of hormone-responsive breast cancer in postmenopausal women.

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“…It is possible that such conjugation might weaken the ability of the cyano group at the 2-position to function as a hydrogen bond acceptor, which has been attributed to be an important factor for strong binding of nonsteroidal AIs bearing a cyano group similar to that of letrozole. 27 As shown in Table 1, 18 is relatively the weakest STS inhibitor among its congeners (12-17). Since hybrids 12, 16, and 17 have IC 50 values against STS of the same order of magnitude, this suggests that a fluoro atom or a methoxy group, but not a cyano group, substituted at the 4 0 -position is better tolerated by STS in this subgroup of compounds.…”

mentioning

confidence: 98%

Hybrid Dual Aromatase-Steroid Sulfatase Inhibitors with Exquisite Picomolar Inhibitory Activity

Woo

Bubert

Purohit

et al. 2010

ACS Med. Chem. Lett.

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Single agents against multiple drug targets are highly topical. Hormonedependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and steroid sulfatase (STS), and several dual aromatase-sulfatase inhibitors (DASIs) have been recently reported. The best compounds from two leading classes of DASI, 3 and 9, are low nanomolar inhibitors. In search of a novel class of DASI, core motifs of two leading classes were combined to give a series of hybrid structures, with several compounds showing markedly improved dual inhibitory activities in the picomolar range in JEG-3 cells. Thus, DASIs 14 (IC 50 : aromatase, 15 pM; STS, 830 pM) and 15 (IC 50 : aromatase, 18 pM; STS, 130 pM) are the first examples of an exceptional new class of highly potent dual inhibitor that should encourage further development toward multitargeted therapeutic intervention in HDBC.KEYWORDS: Hybrid, dual inhibitors, aromatase, sulfatase, cancer E strogen deprivation has been an effective therapeutic intervention for hormone-dependent breast cancer (HDBC). One established and clinically proven approach involves the inhibition of the aromatase enzyme, 1-3 although the inhibition of steroid sulfatase (STS) is an emerging new strategy, as demonstrated by promising results for STX64 (Irosustat, BN83495), [4][5][6] the first STS inhibitor that entered clinical trials. Since both aromatase and STS are targets for treating HDBC, it has been reasoned that estrogen deprivation may be more comprehensively achieved by dual inhibition of both enzymes.Designing single agents that act against multiple biological targets is of increasing interest and prominence. In recent years, an increasing volume of work has been published exemplifying the successful use of this strategy. [7][8][9][10][11][12][13][14][15][16][17] We have pioneered this approach to augment our strategy directed at the first-in-class clinical target of STS inhibition and successfully developed three series of single agent dual aromatase and sulfatase inhibitors (DASIs) that are sulfamate derivatives of the nonsteroidal aromatase inhibitor (AI) 4-((4-bromobenzyl)-[1,2,4]-triazol-4-ylamino)benzonitrile (1) (e.g., 2 and 3), 18-20 letrozole 4 (e.g., 5), 21,22 and anastrozole 6 (e.g., 7) (Figure 1). 23 The design of these DASIs shares a common principle of engendering the irreversible STS inhibitory pharmacophore (ie. an aryl sulfamate ester, ArOSO 2 NH 2 ) into a clinical or experimental AI with minimal structural change incurred on the original scaffold in order to retain and maximize aromatase inhibition. More recently, a different design approach was employed. A series of biphenyl-based DASIs was developed as a result of incorporating the reversible aromatase inhibitory pharmacophore, which is principally a heme-ligating nitrogen-containing heterocycle, into a known sulfamate-based STS inhibitor (e.g., 8 and 9, Figure 1). 24 On evaluating the lead candidates from these four structural classes of DASI, all of them showed in vitro and in vivo dual inhibito...

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Aromatase inhibitors: synthesis, biological activity, and binding mode of azole-type compounds

Cited by 100 publications

References 15 publications

The Vascular Endothelial Growth Factor Receptor Inhibitor PTK787/ZK222584 Inhibits Aromatase

The Vascular Endothelial Growth Factor Receptor Inhibitor PTK787/ZK222584 Inhibits Aromatase

The discovery and mechanism of action of letrozole

Hybrid Dual Aromatase-Steroid Sulfatase Inhibitors with Exquisite Picomolar Inhibitory Activity

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