Irosustat(Irosustat) - 药物靶点：STS_专利_临床

概要

基本信息

药物类型

小分子化药

别名

6-Oxo-8,9,10,11-Tetrahydro-7h-Cyclohepta[C][1]Benzopyran-3-O-Sulfamate、Irostustat、Irosustat (USAN/INN)

+ [8]

靶点

STS

作用方式

抑制剂

作用机制

STS抑制剂(固醇硫酸酯酶抑制剂)

治疗领域

肿瘤皮肤和肌肉骨骼疾病泌尿生殖系统疾病+ [1]

在研适应症-

非在研适应症

ER阳性子宫内膜癌ER阳性乳腺癌HER2阳性乳腺癌+ [4]

原研机构

Ipsen SA

在研机构-

非在研机构

Ipsen SA

Peter MacCallum Cancer Institute

权益机构-

最高研发阶段终止临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C14H15NO5S

InChIKeyDSLPMJSGSBLWRE-UHFFFAOYSA-N

CAS号288628-05-7

关联

8

项与 Irosustat 相关的临床试验

NCT01785992

/ Completed临床2期IIT

A Phase II Study to Assess the Safety and Efficacy of the Steroid Sulfa-tase Inhibitor Irosustat When Added to an Aromatase Inhibitor in ER Positive Locally Advanced or Metastatic Breast Cancer Patients.

70% of breast cancers that occur in postmenopausal women rely on the hormone oestrogen to grow and are likely to respond to hormone treatment. This type of treatment reduces the amount of oestrogen in the body, slowing the growth of cancer or stopping it altogether. One type of hormone treatment, aromatase inhibitors (AIs), works by stopping the body from making oestrogen. Currently, women with locally advanced or metastatic breast cancer that is not being controlled by one class of AI are switched to the other class of AI. The reason for this is that some cancer cells can become resistant to one class but are still sensitive to the other class. However, oestrogen can be made in the body by two pathways and AIs block only one of these pathways. A new drug called Irosustat can reduce the production of oestrogen in the body by blocking the second pathway. This study is investigating whether adding Irosustat to AI treatment i.e. blocking both pathways at the same time, can further reduce the amount of oestrogen in the body and therefore control the breast cancer better.
27 postmenopausal women with oestrogen receptor positive locally advanced or metastatic breast cancer that is not being controlled by their current AI treatment will be recruited in this study from 9 United Kingdom (UK) hospitals. Eligible patients will receive 40mg of Irosustat once daily in addition to the AI on which they progressed. Patients will receive Irosustat for as long as it controls their cancer or until they have side effects that stop them from taking treatment. Patients will be seen monthly for the first 6 months and every 3 months thereafter. Participating patients will also be given the option to take part in the exploratory part of this study by donating tissue and blood samples.

开始日期2012-10-01

申办/合作机构

Imperial College London

[+1]

NCT01662726

/ Terminated临床2期IIT

A Phase II, Open Label, Preoperative Study to Assess the Efficacy of the Novel Steroid Sulfatase Inhibitor Irosustat in Postmenopausal Women With Early Oestrogen Receptor Positive Breast Cancer

This study is investigating the effects of a new hormone treatment for breast cancer called Irosustat. Seventy percent of breast cancers in post-menopausal wome rely on oestrogen to grow therefore are likely to respond to hormone therapy. Irosustat blocks a different pathway of steroid synthesis to Aromatase, reducing in this way oestrogen levels in the body. As less oestrogen reaches the breast cancer, it grows more slowly or stops growing altogether.
IPET will recruit postmenopausal women with early, hormone sensitive, treatment naive breast cancer will receive 40mg of Irosustat once daily for 2 weeks. The effects of Irosustat on breast cancer will be evaluated by PET scans (Positron Emission Tomography) using a radioactive substance called FLT as a tracer. The scans will be performed in a PET-CT scanner which combines a PET scan and a CT scan (Computer Tomography) into one scan. This type of scan can show how body tissues are working, as well as what they look like. FLT-PET scans will be performed before and following treatment with Irosustat. As cancer cells grow faster than the normal cells around them, they will take up more of the radioactive substance, and so stand out clearly on the scan. If Irosustat is slowing down the cancer growth, the cancer will take up less of the tracer.
Blood samples will be taken at regular intervals to assess what the new drug does to the body and the safety and tolerability of Irosustat will be assessed. The study incorporates translation aspects/endpoints which are based on the collection of tumour biopsies before and after treatment with Irosustat although the later biopsy is not mandatory.

开始日期2012-08-01

申办/合作机构

Imperial College London

[+5]

NCT01230970

/ Terminated临床2期

A Phase II, Open-label, Exploratory Study to Assess the Short Term Intratumoural and Peripheral Effects of BN83495 Administered for 14 Days Prior to Surgery to Postmenopausal Women With Newly Diagnosed Primary Invasive Oestrogen Receptor Positive Breast Cancer

This trial will assess the intratumoural pharmacological activity of BN83495 by changes in intratumoural levels of sex hormones and associated inhibition of steroid sulphatase (STS) activity.

开始日期2011-05-01

申办/合作机构

Ipsen SA

100 项与 Irosustat 相关的临床结果

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100 项与 Irosustat 相关的转化医学

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100 项与 Irosustat 相关的专利（医药）

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125

项与 Irosustat 相关的文献（医药）

2025-07-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Novel nonsteroidal steroid sulfatase inhibitors containing glutamic acid unit

Article

作者: Czubak, Paweł ; Biernacki, Karol ; Demkowicz, Sebastian ; Daśko, Mateusz ; Rachon, Janusz ; Ciupak, Olga ; Martyna, Aleksandra ; Masłyk, Maciej ; Datta, Magdalena ; Kubiński, Konrad ; Rak, Janusz

In the present work, we designed and successfully synthesized novel steroid sulfatase (STS) inhibitors based on coumarin, tyramine, triazole, and flavone cores with an additional glutamic acid residue in the structure. The molecular modeling studies revealed that designed derivatives have potential to bind to the molecular target active site, at least theoretically. The biological activity of synthesized compounds was evaluated under a two-step procedure including enzymatic assay and cellular studies using human choriocarcinoma JEG-3 cells. Among the synthesized compounds, the derivative 54E was the most active in both enzymatic and cellular experiments. This result agreed with the molecular modeling data, which indicated that derivative 54E demonstrates the highest affinity to the STS active site. In the enzymatic assay, the remaining STS activity values of 12.97, 17.58, and 20.52 % were observed at 10, 1, and 0.1 μM concentrations of compound 54E, respectively. The IC₅₀ value of 22 nM determined in an experiment with JEG-3 cells for compound 54E was close to the IC₅₀ value determined for the reference STS inhibitor Irosustat (2.7 nM). During the evaluation of the uptake mechanism of the compound 54E, we found that organic anion transporting polypeptides (OATPs) may be responsible for its internalization into the cells. Furthermore, the incubation of zebrafish larvae with the compound 54E revealed no detectable toxic effects in vivo indicating that the compound 54E is a very promising candidate for further preclinical investigations.

2024-10-01·STEROIDS

Steroid sulfatase in mouse liver and testis: Characterization, ontogeny and localization

Article

作者: Selcer, Kyle W ; Balasubramonian, Barathi

Steroid hormones often circulate in the plasma as inactive sulfated forms, such as estrone sulfate and dehydroepiandrosterone sulfate. The enzyme steroid sulfatase (STS) converts these steroids into active forms, mainly estrogens, in peripheral tissues. STS is present in most tissues, but it occurs at higher levels in certain organs, notably liver and placenta. In this study, we examined the tissue distribution of STS in a prominent laboratory model, the house mouse (Mus musculus). Tissues included were heart, liver, small intestine, skeletal muscle, and gonads of both sexes. An ³H-estrone-sulfate conversion assay was used to measure STS activity in tissue homogenates and extracts. STS activities were high for hepatic tissue homogenates of both genders. Testicular STS levels were similar to those of liver, while STS activities of ovary, small intestine, heart, and muscle were considerably lower. The specific STS inhibitors, EMATE and STX-64 virtually eliminated STS activity in hepatic microsomes and cytosols, verifying that the observed enzyme activity was due to STS. Enzyme kinetic assays showed Km values of 8.6 µM for liver and 9.1 µM for testis, using E₁S as substrate. Hepatic and testicular STS activities, measured in CHAPS-extracted microsome, were low up to 5 weeks of age and were higher through 56 weeks. Western blotting, with a specific STS antibody, confirmed the presence of STS protein (65 Da) in both liver and testis. Immunofluorescence of tissue sections detected the presence of STS protein in hepatocytes, in testicular Leydig cells and in seminiferous tubules (Leydig cells and developing germ cells). These results suggest that STS may have a significant role in testicular function.

2024-10-01·ARCHIV DER PHARMAZIE

An overview of the latest outlook of sulfamate derivatives as anticancer candidates (2020–2024)

Review

作者: Alajmi, Aljawhra A. ; Alrashed, Aishah S. ; Mustafa, Esra M. ; Shahin, Afnan I. ; Hashem, Omar ; Bahaaddin, Aesheh H. ; Anbar, Hanan S. ; El‐Gamal, Mohammed I.

Abstract:

Considering the emergence of new anticancer drugs, in this review we emphasized and highlighted the recent reports and advances related to sulfamate‐incorporating compounds with potential anticancer activity during the last 5 years (2020–2024). Additionally, we discussed their structure–activity relationship, clarifying their potent bioactivity as anticancer agents. Sulfamate derivatives hold promise as effective therapeutic candidates against cancer. By targeting biological targets associated with the development of cancer, such as steroid sulfatases (STS), carbonic anhydrases (CAs), microtubules, NEDD8‐activating enzyme, small ubiquitin‐like modifiers (SUMO)‐activating enzyme (SAE), cyclin‐dependent kinases (CDKs), breast cancer susceptibility gene 1 (BRCA1), and so on, this can furnish small molecules as anticancer lead candidates serving the drug discovery field. For example, compound 2, an STS inhibitor, demonstrated superior activity compared to its reference, irosustat, by fivefold. In addition, compound 21, an SAE, is under phase I clinical trials. Continued research into sulfamate derivatives holds potential for the development of novel therapeutic agents targeting various diseases.

100 项与 Irosustat 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D09915	Irosustat	-	DB02292

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
ER阳性乳腺癌	临床2期	挪威	Ipsen SA	2011-05-01
ER阳性子宫内膜癌	临床2期	美国	Ipsen SA	2010-11-01
ER阳性子宫内膜癌	临床2期	加拿大	Ipsen SA	2010-11-01
复发性子宫内膜癌	临床2期	美国	Ipsen SA	2009-08-01
复发性子宫内膜癌	临床2期	比利时	Ipsen SA	2009-08-01
复发性子宫内膜癌	临床2期	捷克	Ipsen SA	2009-08-01
复发性子宫内膜癌	临床2期	法国	Ipsen SA	2009-08-01
复发性子宫内膜癌	临床2期	匈牙利	Ipsen SA	2009-08-01
复发性子宫内膜癌	临床2期	拉脱维亚	Ipsen SA	2009-08-01
复发性子宫内膜癌	临床2期	立陶宛	Ipsen SA	2009-08-01

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01785992 (IRIS, Pubmed) 人工标引	临床2期	ER阳性乳腺癌二线 ER-positive	27	Irosustat	艱顧選顧襯廠鹹蓋壓齋(鏇齋醖糧艱醖廠膚艱簾) = 鑰襯夢築選淵鹽夢膚鑰構醖糧範簾獵衊襯醖製 (廠選襯願淵範齋顧網鬱, 6.3 ~ 38.1) 更多	积极	2017-09-01
NCT00910091 (Pubmed \| Int J Gynecol Cancer) 人工标引	临床2期	子宫内膜癌	71	irosustat	蓋遞選鑰獵鬱廠觸鹽餘(範糧窪襯餘積餘網觸積) = 壓顧壓繭簾選構蓋觸觸鑰網襯壓獵壓願衊艱願 (糧艱製遞簾餘夢鏇鏇廠 ) 更多	不佳	2017-02-01
NCT00910091 (Pubmed \| Int J Gynecol Cancer) 人工标引	临床2期	子宫内膜癌	71	megestrol acetate	蓋遞選鑰獵鬱廠觸鹽餘(範糧窪襯餘積餘網觸積) = 鬱膚艱襯鹽鹽獵觸壓餘鑰網襯壓獵壓願衊艱願 (糧艱製遞簾餘夢鏇鏇廠 ) 更多	不佳	2017-02-01
NCT01662726 (ASCO2016)	临床2期	ER阳性乳腺癌	13	Irosustat 40mg once daily	憲淵憲積淵築壓築憲選(獵簾觸廠鏇願衊構製遞) = 選廠觸壓網選築蓋壓鏇範醖膚艱積窪獵餘鹹製 (鏇繭觸築獵襯願艱範憲, -29.9 ~ 48.2) 更多	积极	2016-05-20
NCT01785992 (IRIS, ASCO2016)	临床2期	ER阳性乳腺癌一线	27	Irosustat + AI	觸繭願壓餘醖鏇膚製製(網餘憲鹽範製範夢衊壓) = 7% 衊網衊願糧夢鬱淵糧築 (襯範範繭蓋網製膚膚獵 ) 更多	积极	2016-05-20
NCT00910091 (CTgov)	临床2期	复发性子宫内膜癌	73	BN83495 (A- BN 83495- 40mg)	範憲鑰鹽顧餘繭築鬱膚(觸淵積構衊願夢餘壓築) = 鑰築顧繭鏇繭艱衊壓糧艱築製鹹觸鑰襯鏇繭餘 (蓋鹹衊夢鬱積獵簾繭廠, 鬱憲遞鹹襯鹽壓齋鬱衊 ~ 鬱窪築鏇構鏇糧鑰獵簾) 更多	-	2015-09-30
NCT00910091 (CTgov)	临床2期	复发性子宫内膜癌	73	Megestrol Acetate+MA (B- MA - 160mg)	範憲鑰鹽顧餘繭築鬱膚(觸淵積構衊願夢餘壓築) = 繭選選鑰膚襯選餘窪齋艱築製鹹觸鑰襯鏇繭餘 (蓋鹹衊夢鬱積獵簾繭廠, 鏇鑰選繭範艱憲膚築艱 ~ 願蓋鑰壓壓鹹觸鑰觸鏇) 更多	-	2015-09-30
NCT01251354 (CTgov)	临床2期	ER阳性子宫内膜癌	6	BN83495	構膚觸窪網積艱鹹鬱衊 = 積範鏇壓鏇膚醖淵範襯憲窪製簾製簾繭夢膚顧 (醖夢構鑰蓋憲觸襯壓淵, 積選衊鹽醖選壓範願製 ~ 繭衊積壓艱觸鏇醖廠醖) 更多	-	2015-09-02