Irosustat (STX64)
(Synonyms: STX64; BN83495; 667-Coumate) 目录号 : GC33105
A steroid sulfatase inhibitor
Cas No.:288628-05-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | MCF-7 cells are cultured in growth medium (minimum essential medium (MEM) containing, phenol red, 10% foetal calf serum (FCS) and essential nutrients). When the cells reach 60% confluency, they are treated with Irosustat (0.001-10 μM) in growth medium. After 72 h of incubation, photographs are taken under normal conditions of light and the number of attached cells in each flask is determined using a Coulter cell counter[2]. |
Animal experiment: | Rats[1]Ludwig rats bearing mammary tumors are used in the assay. Tumor development is monitored, and animals are ovariectomized when tumors reach 0.8-1.5 cm in diameter. Tumors are allowed to regress over a 12- to 13-day period to confirm their hormone-dependent status. Regrowth of tumors is stimulated with oestrone sulfate (E1S; 50 μg/day, s.c.). When tumors have regrown, animals continue to receive either E1S alone or E1S plus Irosustat at 10 mg/kg/day or 2 mg/kg/day, p.o., until tumor regression has occurred. Tumor volumes are calculated from two measured diameters[1]. |
References: [1]. Purohit A, et al. In vivo inhibition of estrone sulfatase activity and growth of nitrosomethylurea-induced mammary tumors by 667 COUMATE. Cancer Res. 2000 Jul 1;60(13):3394-6. | |
STX-64 is a steroid sulfatase inhibitor (IC50 = 0.008 ?M in placental microsomes).1 It also inhibits carbonic anhydrase II (CAII; IC50 = 0.025 ?M).2 STX-64 inhibits LPS-induced production of nitric oxide (NO) and prostaglandin E2 in RAW 264.7 macrophages (IC50s = 85.76 and 0.081 ?M, respectively).3 It reduces rat liver steroid sulfatase activity when administered at a dose of 1 mg/kg.1 STX-64 (2 mg/kg) inhibits estrone sulfate-induced uterine growth and reduces the growth of N-nitroso-N-methylurea-induced, estrone sulfate-maintained mammary tumors in ovariectomized rats.4
1.Malini, B., Purohit, A., Ganeshapillai, D., et al.Inhibition of steroid sulphatase activity by tricyclic coumarin sulphamatesJ. Steroid Biochem. Mol. Biol.75(4-5)253-258(2000) 2.Ho, Y.T., Purohit, A., Vicker, N., et al.Inhibition of carbonic anhydrase II by steroidal and non-steroidal sulphamatesBiochem. Biophys. Res. Commun.305(4)909-914(2003) 3.Jang, H.-L., El-Gamal, M.I., Choi, H.-E., et al.Synthesis of tricyclic fused coumarin sulfonates and their inhibitory effects on LPS-induced nitric oxide and PGE2 productions in RAW 264.7 macrophagesBioorg. Med. Chem. Lett.24(2)571-575(2014) 4.Purohit, A., Woo, L.W., Potter, B.V., et al.In vivo inhibition of estrone sulfatase activity and growth of nitrosomethylurea-induced mammary tumors by 667 COUMATECancer Res.60(13)3394-3396(2000)
| Cas No. | 288628-05-7 | SDF | |
| 别名 | STX64; BN83495; 667-Coumate | ||
| Canonical SMILES | O=C1OC2=CC(OS(=O)(N)=O)=CC=C2C3=C1CCCCC3 | ||
| 分子式 | C14H15NO5S | 分子量 | 309.34 |
| 溶解度 | DMSO : ≥ 150 mg/mL (484.90 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.2327 mL | 16.1634 mL | 32.3269 mL |
| 5 mM | 0.6465 mL | 3.2327 mL | 6.4654 mL |
| 10 mM | 0.3233 mL | 1.6163 mL | 3.2327 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
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计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Irosustat: a first-generation steroid sulfatase inhibitor in breast cancer
Expert Rev Anticancer Ther 2011 Feb;11(2):179-83.PMID:21342037DOI:10.1586/era.10.201.
Endocrine therapy is a key modality in the management of breast cancer, with current options for postmenopausal women including tamoxifen, aromatase inhibitors and fulvestrant. Unfortunately, in spite of these advances, many women still relapse or progress on endocrine therapy. Given that resistance (de novo or acquired resistance) is a major limiting factor in the use of endocrine therapy, additional endocrine therapies with novel methods of action are required. Steroid sulfatase, which is responsible for the conversion of estrone sulfate to estrone, as well as dehydroepiandrosterone sulfate to dehydroepiandrosterone, has been implicated in endocrine resistance. In this article, we summarize the preclinical and clinical data to support the potential role of steroid sulfatase in breast cancer, as well as the current data on the first available steroid sulfatase inhibitor named Irosustat (STX64; 667 Coumate; BN83495), and discuss its potential clinical development.
Structure-activity relationship for the first-in-class clinical steroid sulfatase inhibitor Irosustat (STX64, BN83495)
ChemMedChem 2011 Nov 4;6(11):2019-34.PMID:21990014DOI:10.1002/cmdc.201100288.
Structure-activity relationship studies were conducted on Irosustat (STX64, BN83495), the first steroid sulfatase (STS) inhibitor to enter diverse clinical trials for patients with advanced hormone-dependent cancer. The size of its aliphatic ring was expanded; its sulfamate group was N,N-dimethylated, relocated to another position and flanked by an adjacent methoxy group; and series of quinolin-2(1H)-one and quinoline derivatives of Irosustat were explored. The STS inhibitory activities of the synthesised compounds were assessed in a preparation of JEG-3 cells. Stepwise enlargement of the aliphatic ring from 7 to 11 members increases potency, although a further increase in ring size is detrimental. The best STS inhibitors in vitro had IC50 values between 0.015 and 0.025 nM. Other modifications made to Irosustat were found to either abolish or significantly weaken its activity. An azomethine adduct of Irosustat with N,N-dimethylformamide (DMF) was isolated, and crystal structures of Irosustat and this adduct were determined. Docking studies were conducted to explore the potential interactions between compounds and the active site of STS, and suggest a sulfamoyl group transfer to formylglycine 75 during the inactivation mechanism.
SULFATION PATHWAYS: A role for steroid sulphatase in intracrine regulation of endometrial decidualisation
J Mol Endocrinol 2018 Aug;61(2):M57-M65.PMID:29720512DOI:10.1530/JME-18-0037.
In women, establishment of pregnancy is dependent upon 'fine-tuning' of the endometrial microenvironment, which is mediated by terminal differentiation (decidualisation) of endometrial stromal fibroblasts (ESFs). We have demonstrated that intracrine steroid metabolism plays a key role in regulating decidualisation and is essential for time-dependent expression of key factors required for endometrial receptivity. The primary aim of the current study was to determine whether sulphated steroids can act as precursors to bioactive sex steroids during decidualisation. We used primary human ESF and a robust in vitro model of decidualisation to assess the expression of genes associated with sulphation, desulphation and transport of sulphated steroids in human ESF as well as the impact of the steroid sulphatase (STS) inhibitor STX64 (Irosustat). We found evidence for an increase in both expression and activity of STS in response to a decidualisation stimulus with abrogation of oestrone biosynthesis and decreased secretion of the decidualisation marker IGFBP1 in the presence of STX64. These results provide novel insight into the contribution of STS to the intracrine regulation of decidualisation.
Steroid Sulphatase and Its Inhibitors: Past, Present, and Future
Molecules 2021 May 11;26(10):2852.PMID:34064842DOI:10.3390/molecules26102852.
Steroid sulphatase (STS), involved in the hydrolysis of steroid sulphates, plays an important role in the formation of both active oestrogens and androgens. Since these steroids significantly impact the proliferation of both oestrogen- and androgen-dependent cancers, many research groups over the past 30 years have designed and developed STS inhibitors. One of the main contributors to this field has been Prof. Barry Potter, previously at the University of Bath and now at the University of Oxford. Upon Prof. Potter's imminent retirement, this review takes a look back at the work on STS inhibitors and their contribution to our understanding of sulphate biology and as potential therapeutic agents in hormone-dependent disease. A number of potent STS inhibitors have now been developed, one of which, Irosustat (STX64, 667Coumate, BN83495), remains the only one to have completed phase I/II clinical trials against numerous indications (breast, prostate, endometrial). These studies have provided new insights into the origins of androgens and oestrogens in women and men. In addition to the therapeutic role of STS inhibition in breast and prostate cancer, there is now good evidence to suggest they may also provide benefits in patients with colorectal and ovarian cancer, and in treating endometriosis. To explore the potential of STS inhibitors further, a number of second- and third-generation inhibitors have been developed, together with single molecules that possess aromatase-STS inhibitory properties. The further development of potent STS inhibitors will allow their potential therapeutic value to be explored in a variety of hormone-dependent cancers and possibly other non-oncological conditions.
Development of steroid sulfatase inhibitors
Mol Cell Endocrinol 2011 Jul 4;340(2):175-85.PMID:21238537DOI:10.1016/j.mce.2010.12.035.
Hydrolysis of biologically inactive steroid sulfates to unconjugated steroids by steroid sulfatase (STS) is strongly implicated in rendering estrogenic stimulation to hormone-dependent cancers such as those of the breast. Considerable progress has been made in the past two decades with regard to the discovery, design and development of STS inhibitors. We outline historical aspects of their development, cumulating in the discovery of the first clinical trial candidate STX64 (BN83495, Irosustat) and other sulfamate-based inhibitors. The development of reversible STS inhibitors and the design of dual inhibitors of both aromatase and STS is also discussed.