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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97

项与 Irosustat 相关的文献（医药）

2027-02-01·JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY

Comparative in silico evaluation of steroidal and non-steroidal sulfamates as potential human steroid sulfatase inhibitors

Article

作者: Amin, Abdalla Ali ; Abdalla, Bahez Ahmed ; Abdlrahman, Roz Goran ; Qader, Rebaz Abdulazeez ; Ibrahim, Zana Hassan ; Ali, Ayad Kareem

Steroid sulfatase (STS) is a membrane-bound enzyme and a key therapeutic target for hormone-dependent disorders. This study evaluates four sulfamate-based STS inhibitors Coumate, Irosustat (STX64), STX213, and STX1938 across both the catalytic core (Site 1) and the secondary membrane-gate vestibule (Site 2) of human STS (hSTS; PDB ID: 8EG3). Molecular docking and molecular dynamics (MD) simulations were integrated with Prime MM-GBSA energetic calculations, residue contact mapping, and computational ADMET profiling. At the catalytic site, key interactions with formylglycine (FGly75), Lys368, His290, and Phe178 were maintained, though bulky steroidal frameworks experienced structural displacement. Conversely, the membrane-gate vestibule offered a hydrophobic environment that facilitated sustained ligand retention. Irosustat exhibited the most favorable trajectory-averaged MM-GBSA binding score at Site 1 (-408.6 kcal/mol), whereas Irosustat and STX1938 demonstrated comparable affinities at Site 2 (-390.4 and -389.0 kcal/mol, respectively), with STX1938 establishing particularly dense, persistent vestibule contacts. These computational findings suggest that the membrane-gate vestibule may act as a dynamically stable retention site predicted to modulate inhibitor passage into the catalytic core. Site-2 occupancy is thus proposed as a putative gatekeeper mechanism to guide future experimental validation and inhibitor design.

2026-02-12·ACS Medicinal Chemistry Letters

Synthesis and Biological Evaluation of 3,5-Diaryl-Substituted 1,2,4-Oxadiazole Sulfamates as Potent Steroid Sulfatase Inhibitors

Article

作者: Szwarc-Karabyka, Katarzyna ; Rak, Janusz ; Daśko, Mateusz ; Czubak, Paweł ; Martyna, Aleksandra ; Masłyk, Maciej ; Biernacki, Karol ; Ciupak, Olga ; Grobelna, Agata ; Rachoń, Janusz ; Kubiński, Konrad ; Kwaśnik, Mateusz ; Demkowicz, Sebastian ; Mirocki, Artur

A novel series of 3,5-disubstituted 1,2,4-oxadiazole sulfamates was synthesized and evaluated as steroid sulfatase (STS) inhibitors. Molecular docking predicted high affinity (binding energies of up to -8.9 kcal·mol^-1), often surpassing the reference Irosustat. Biological evaluation confirmed potent inhibition; compound 9n reduced enzymatic STS activity to 3.5% at 10 μM. In JEG-3 cells, the most potent derivative, 9j, exhibited an IC₅₀ of 6.64 nM, comparable to that of Irosustat (4.19 nM). Structure-activity relationship analysis revealed that the substitution pattern of the oxadiazole heterocycle plays a decisive role in determining biological activity. Shifting the aryl-sulphamate pharmacophore between positions 3- and 5- of the 1,2,4-oxadiazole heterocycle is crucial for maintaining high biological activity. These findings establish 3,5-disubstituted 1,2,4-oxadiazole sulfamates as promising leads for treating hormone-dependent cancers.

2026-01-01·BREAST CANCER RESEARCH AND TREATMENT

Assessing endocrine resistance: monitoring circulating ESR1 mutations in Irosustat-treated ER positive breast cancer

Article

作者: Allsopp, Rebecca C ; Coombes, R Charles ; Palmieri, Carlo ; Wadsley, Marc K ; Luo, Jin-Li ; Page, Karen ; Acheampong, Emmanuel ; Hastings, Robert K ; Martinson, Luke J ; Shaw, Jacqueline A

Abstract:

Purpose:

We aimed to investigate the prevalence and spectrum of ESR1 mutations alongside cell-free DNA (cfDNA) dynamics in patients with estrogen receptor-positive metastatic breast cancer recruited to the phase II IRIS study who had progressed on first-line aromatase inhibitor (AI) therapy and then continued their AI in combination with Irusostat (40 mg), an irreversible steroid sulfatase inhibitor.

Methods:

cfDNA was isolated from 96 serial plasma samples from 24 patients, alongside primary tumour DNA ( n = 16), and analysed by next-generation sequencing using a custom-designed mutation panel on the Illumina NovaSeq platform.

Results:

Thirteen of 16 tumour DNA samples harboured at least one somatic mutation across nine genes. Twenty one of the 24 patients (88%) had at least one somatic mutation in cfDNA (248 total mutations across 10 genes). Circulating tumour DNA ESR1 mutations (ct ESR1 m) were the most prevalent, present in 16 patients (76%) with both stable (SD) and progressive disease (PD), showing no clear association with disease progression. Eleven patients had polyclonal ct ESR1 m within the ligand-binding domain, six at baseline, while five harboured a single ct ESR1 m variant. Five other patients acquired polyclonal mutations over treatment.

Conclusions:

Analysis of serial plasma samples revealed highly dynamic ct ESR1 m during AI treatment and frequent detection of polyclonal ct ESR1 m in patients (both with SD and PD) recruited to the IRIS study. These findings, albeit in a limited sample size, underscore the challenge of targeting a single ESR1 mutation and emphasise the need for careful patient selection, specifically those with wild-type ESR1 , in trials investigating sequential estrogen-lowering therapies.

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	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
复发性子宫内膜癌	临床2期	摩尔多瓦	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	遞鏇積窪餘糧繭膚製鏇(廠艱餘範鑰繭築範網鬱) = 積獵願顧鹹襯衊鑰構築鬱簾蓋淵構簾鑰膚壓窪 (願壓淵製壓鏇鬱夢夢鹽, 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	餘醖夢觸鹹鑰衊積廠觸(網艱遞齋鹽衊遞淵選衊) = 願憲鏇鬱製衊蓋顧衊糧選蓋選獵憲顧鑰鹽膚壓 (鏇願壓顧夢鹽選廠鹹淵 ) 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	餘醖夢觸鹹鑰衊積廠觸(網艱遞齋鹽衊遞淵選衊) = 艱選製鹹範鏇顧壓製壓選蓋選獵憲顧鑰鹽膚壓 (鏇願壓顧夢鹽選廠鹹淵 ) 更多	不佳	2017-02-01
NCT01785992 (IRIS, ASCO2016)	临床2期	ER阳性乳腺癌一线	27	Irosustat + AI	鹹鬱製醖鬱鬱觸憲廠鏇(蓋鏇積窪觸構鑰淵窪範) = 7% 夢鏇鏇鬱簾窪範窪範膚 (構積製襯遞積鹹鹽願鏇 ) 更多	积极	2016-05-20
NCT01662726 (ASCO2016)	临床2期	ER阳性乳腺癌	13	Irosustat 40mg once daily	鹹夢膚製鹹淵簾夢壓簾(製繭簾鹹鏇構衊衊鏇憲) = 鹽淵鹹範範繭鹹醖糧願製壓鬱構餘膚鹽構鹽鑰 (鏇鹹選壓遞淵糧範鑰鑰, -29.9 ~ 48.2) 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)	繭鏇願齋製選選網獵窪(襯壓窪網繭鹽製遞鏇築) = 願壓壓艱選鏇餘網觸鏇鬱鏇鏇積鏇艱鏇選觸獵 (鏇網蓋選構鏇鏇遞醖艱, 廠廠齋壓廠窪築鏇網獵 ~ 觸築製艱膚觸築憲夢繭) 更多	-	2015-09-30
NCT00910091 (CTgov)	临床2期	复发性子宫内膜癌	73	Megestrol Acetate (B- MA - 160mg)	繭鏇願齋製選選網獵窪(襯壓窪網繭鹽製遞鏇築) = 選艱憲製膚壓淵簾構構鬱鏇鏇積鏇艱鏇選觸獵 (鏇網蓋選構鏇鏇遞醖艱, 壓顧窪鬱遞齋鏇壓衊鹹 ~ 鑰簾鑰獵遞顧淵範廠簾) 更多	-	2015-09-30
NCT01251354 (CTgov)	临床2期	ER阳性子宫内膜癌	6	BN83495	淵餘網鹽蓋願糧願憲餘 = 糧齋廠遞鹹簾鏇蓋選鏇襯壓壓獵簾膚築蓋窪淵 (鹹淵鏇築鹹壓糧艱廠網, 鑰鑰製膚憲鬱醖簾範顧 ~ 範願簾鹽襯製壓餘簾繭) 更多	-	2015-09-02