Estrone sulfatase and its inhibitors

Department of Pharmacy, School of Pharmacy and Chemistry, Kingston University, Penrhyn Road, Kingston upon Thames, Surrey KT12EE, UK.
Anti-cancer agents in medicinal chemistry (Impact Factor: 2.47). 08/2009; 9(6):599-612.
Source: PubMed


A high proportion (approximately 40%) of breast cancers are hormone-dependent and it is the female hormone estradiol (E2) that is believed to play a key role in the initiation, promotion and progression of this disease. In the fight against this disease, compounds which are potent inhibitors of the cytochrome P-450 enzyme aromatase (AR) (which catalyses the conversion of the C19 androgens to the C18 estrogens) have been the major target. However, the administration of AR inhibitors alone does not prevent the localised biosynthesis of estrone (E1) (and therefore the subsequent synthesis of E2) within breast tumour cells via alternative non-AR routes. This has therefore been the major impetus for the development of steroid sulfatase (E1STS) inhibitors. The E1STS enzyme regulates the formation of E1 from estrone sulfate (E1S), a steroid conjugate present in high concentrations in tissue and blood in women with breast cancer. The STS enzyme has also been shown to catalyse the formation of dehydroepiandrosterone (DHEA) from DHEA-sulfate (DHEAS). This is important since DHEA can be converted to 5-androstene-3beta,17beta-diol, which has been shown to possess weak estrogenic properties, however, due to the high concentration of this steroid, it is able to stimulate the growth of breast cancer cells in vitro and in vivo. Considerable progress has been made in recent years in the development of a number of potent E1STS inhibitors, as such both steroidal and non-steroidal compounds have been considered and a number of highly potent inhibitors have been produced and evaluated against what is now considered a crucial enzyme in the fight against hormone-dependent breast cancer. The review therefore summarises the work that has been undertaken todate.

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    • "It is a metabolic intermediate in the biosynthesis of androgens and estrogens, and it is produced in the adrenal glands and in the gonads. 5-Diol is a metabolite of DHEA (reviewed in [1]), and 3β-Adiol is metabolized from 5α- dihydrotestosterone (reviewed in [39]). E2 is the most abundant and potent endogenous estrogen in female vertebrates during the reproductive years. "
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    • "E1S is a steroid conjugate present in high concentrations in tissue and blood in women with breast cancer. E1S is considered an important source for the formation of active estrogens which is able to be produced by STS activity (Aidoo-Gyamfi et al., 2009). "
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