Delving into the Latest Updates on Irosustat with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

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

+ [8]

Target

STS

Mechanism

STS inhibitors(Steryl-sulfatase inhibitors)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal DiseasesUrogenital Diseases+ [1]

Active Indication-

Inactive Indication

Endometrial CarcinomaER Positive Endometrial CarcinomaEstrogen receptor positive breast cancer+ [2]

Originator Organization

Ipsen SA

Active Organization-

Inactive Organization

Ipsen SA

Peter MacCallum Cancer Institute

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

Structure

Molecular FormulaC14H15NO5S

InChIKeyDSLPMJSGSBLWRE-UHFFFAOYSA-N

CAS Registry288628-05-7

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.

Start Date01 Oct 2012

Sponsor / Collaborator

Imperial College London

[+1]

NCT01662726 / TerminatedPhase 2IIT

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.

Start Date01 Aug 2012

Sponsor / Collaborator

Imperial College London

[+6]

NCT01230970 / TerminatedPhase 2

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.

Start Date01 May 2011

Sponsor / Collaborator

Ipsen SA

100 Clinical Results associated with Irosustat

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100 Translational Medicine associated with Irosustat

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100 Patents (Medical) associated with Irosustat

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92

Literatures (Medical) associated with Irosustat

21 Dec 2023·Journal of biomolecular structure & dynamics

Dual aromatase-steroid sulfatase inhibitors (DASI's) for the treatment of breast cancer: a structure guided ligand based designing approach

Article

Author: Singh, Yogesh ; Thareja, Suresh ; Verma, Sant Kumar ; Jaswal, Shalini ; Singh, Satwinder

Dual aromatase-steroid sulfatase inhibitors (DASIs) lead to significant deprivation of estrogen levels as compared to a single target inhibition and thereby exhibited an additive or synergistic effect in the treatment of hormone-dependent breast cancer (HDBC). Triazole-bearing DASI's having structural features of clinically available aromatase inhibitors are identified as lead structures for optimization as DASI's. To identify the spatial fingerprints of target-specific triazole as DASI's, we have performed molecular docking assisted Gaussian field-based comparative 3D-QSAR studies on a dataset with dual aromatase-STS inhibitory activities. Separate contours were generated for both aromatase and steroid sulphates showing respective pharmacophoric structural requirements for optimal activity. These developed 3D-QSAR models also showed good statistical measures with the excellent predictive ability with PLS-generated validation constraints. Comparative steric, electrostatic, hydrophobic, HBA, and HBD features were elucidated using respective contour maps for selective target-specific favourable activity. Furthermore, the molecular docking was used for elucidating the mode of binding as DASI's along with the MD simulation of 100 ns revealed that all the protease-ligand docked complexes are overall stable as compared to reference ligand (inhibitor ASD or Irosustat) complex. Further, the MM-GBSA study revealed that compound 24 binds to aromatase as well as STS active site with relatively lower binding energy than reference complex, respectively. A comparative study of these developed multitargeted QSAR models along with molecular docking and dynamics study can be employed for the optimization of drug candidates as DASI's.Communicated by Ramaswamy H. Sarma.

11 Oct 2023·Journal of periodontal & implant science

Host modulation therapy for improving the osseointegration of dental implants under bone healing-suppressed conditions: a preclinical rodent-model experiment.

Article

Author: Song, Young Woo ; Kwon, Yoon-Hee ; Park, Jin-Young ; Moon, Seok Jun ; Jang, Wooyoung Eric ; Kim, Sung-Jin ; Seo, Jeong Taeg ; Jung, Ui-Won

PURPOSE:

Placing dental implants in areas with low bone density or in conditions where bone healing is suppressed is challenging for clinicians. An experiment using a rodent model was performed with the aim of determining the efficacy of host modulation by increasing the systemic level of cholesterol sulfate (CS) using Irosustat in the context of the bone healing process around dental implants.

METHODS:

In 16 ovariectomised female Sprague-Dawley rats, 2 implant fixtures were placed in the tibial bones (1 fixture on each side). At 1 week after surgery, the high-CS group (n=8) received Irosustat-mixed feed, while the control group (n=8) was fed conventionally. Block specimens were obtained at 5 weeks post-surgery for histologic analysis and the data were evaluated statistically (P<0.05).

RESULTS:

Unlike the high-CS group, half of the specimens in the control group demonstrated severe bone resorption along with a periosteal reaction in the cortex. The mean percentages of bone-to-implant contact (21.5%) and bone density (28.1%) near the implant surface were significantly higher in the high-CS group than in the control group (P<0.05), as was the number of Haversian canals (by 5.3).

CONCLUSIONS:

Host modulation by increasing the CS level may enhance the osseointegration of dental implants placed under conditions of impaired bone healing.

01 Sep 2023·Bioorganic chemistry

Design, structure–activity relationships, and enzyme kinetic studies of tricyclic and tetracyclic coumarin–based sulfamates as steroid sulfatase inhibitors

Article

Author: Liang, Pi-Hui ; Chiu, Pei-Fang ; Lu, Yeh-Lin ; Hsieh, Yves S Y ; Tsai, Keng-Chang ; Lin, I-Chun ; Chan, Hui-Yu ; Lin, Tzung-Shen ; Lin, Mei-Hsiang ; Chang, Chiao-Nien ; Chen, Mei-Jou

Inhibition of steroid sulfatase (STS) decreases estrogen production and thus, suppresses tumor proliferation. Inspired by irosustat, the first STS inhibitor in clinical trials, we explored twenty-one tricyclic and tetra-heterocyclic coumarin-based derivatives. Their STS enzyme kinetic parameters, docking models, and cytotoxicity toward breast cancer and normal cells were evaluated. Tricyclic derivative 9e and tetracyclic derivative 10c were the most promising irreversible inhibitors developed in this study, with K_I of 0.05 and 0.4 nM, and k_inact/K_I ratios of 28.6 and 19.1 nM^-1min^-1 on human placenta STS, respectively.

100 Deals associated with Irosustat

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External Link

KEGG	Wiki	ATC	Drug Bank
D09915	-	-	DB02292

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Estrogen receptor positive breast cancer	Phase 2	NO	Ipsen SA	01 May 2011
ER Positive Endometrial Carcinoma	Phase 2	US	Ipsen SA	01 Nov 2010
ER Positive Endometrial Carcinoma	Phase 2	CA	Ipsen SA	01 Nov 2010
Endometrial Carcinoma	Phase 2	RU	Ipsen SA	01 Aug 2009
Prostatic Cancer	Phase 2	-	Ipsen SA	-
Non-Small Cell Lung Cancer	Phase 1	AU	Peter MacCallum Cancer Institute	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01785992 (IRIS, Pubmed) Manual	Phase 2	Estrogen receptor positive breast cancer Second line ER-positive	27	Irosustat	yykgkfjynh(rdksqkoilq) = mrvogbtjwv bzvjtknlop (varhqexwfl, 6.3 - 38.1) View more	Positive	01 Sep 2017
NCT00910091 (Pubmed \| Int J Gynecol Cancer) Manual	Phase 2	Endometrial Carcinoma	71	irosustat	opjyfykhfm(ksmuftijea) = gxzpvuajlh hhxwwgqrtj (mnopzytgwv ) View more	Negative	01 Feb 2017
NCT00910091 (Pubmed \| Int J Gynecol Cancer) Manual	Phase 2	Endometrial Carcinoma	71	megestrol acetate	opjyfykhfm(ksmuftijea) = kwxdeaqppu hhxwwgqrtj (mnopzytgwv ) View more	Negative	01 Feb 2017
NCT01662726 (ASCO2016)	Phase 2	Estrogen receptor positive breast cancer	13	Irosustat 40mg once daily	edztcdrcwu(awhignifkj) = hkwgrhzjfc peymkwzaam (duvdhrbmtq, -29.9 to 48.2) View more	Positive	20 May 2016
NCT00910091 (CTgov)	Phase 2	Recurrent Endometrial Cancer	73	BN83495 (A- BN 83495- 40mg)	anbhrhllsj(fbwllsljtk) = jvxvrwcihb qgnmubymoi (jjoqyftojq, schlajokpq - shntrpyjxl) View more	-	30 Sep 2015
NCT00910091 (CTgov)	Phase 2	Recurrent Endometrial Cancer	73	Megestrol Acetate (MA) (B- MA - 160mg)	anbhrhllsj(fbwllsljtk) = jvadalinee qgnmubymoi (jjoqyftojq, opwiiprqgj - aljfnwvxmc) View more	-	30 Sep 2015
NCT01251354 (CTgov)	Phase 2	ER Positive Endometrial Carcinoma	6	BN83495	pdilknyroz(tybyqpfjou) = kpqhxpaero jveblaoycm (uwhcwphbmv, elosqpfvpz - evyhjzkclk) View more	-	02 Sep 2015