irosustat (BN 83495) / Ipsen - LARVOL DELTA

Novel nonsteroidal steroid sulfatase inhibitors containing glutamic acid unit. (PubMed, Eur J Med Chem) - "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."

Journal • Oncology

A STEROID SULFATASE INHIBITOR, ONESTX -01, AS A NOVEL TREATMENT FOR NEURODEGENERATIVE DISEASES: EFFECT IN PROGRESSION IN HUNTINGTON DISEASE MODELS (ADPD 2025) - "Aims: ONESTX-01 (formerly Irosustat) is a small molecule that blocks steroid sulfatase (STS), increasing the ratio of sulfated to free steroids in both animals and humans. Preliminary data suggest ONESTX -1 treatment could be a new approach to reversing or alleviating key symptoms in HD patients. The beneficial effect of ONESTX -01 in proteinopathies may be conserved accross evolutionary distant animal models."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Genetic Disorders • Huntington's Disease • Inflammation • Movement Disorders • Proteinopathy

Investigating The Role Of Oestrogens In High-Grade Serous Ovarian Cancer And Platinum Resistance (ESGO 2025) - "The effects of estrogens and sulfatase inhibitor (STX64) on proliferation and migration as well as sensitivity to carboplatin were analysed using the Alamar Blue assay and the wound healing assay. EE2 in combination with carboplatin was more effective in reducing migration in COV362 compared to the individual treatments. Transcriptomic analyses of HGSOC tissues and cell lines identified potential target genes that influence response to treatment.Conclusion This study elucidates the role of oestrogens in proliferation and migration, identifies biomarker candidates for chemoresistance of HGSOC and suggests novel strategies to overcome chemoresistance."

High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor

Steroid sulfatase in mouse liver and Testis: Characterization, ontogeny and localization. (PubMed, Steroids) - "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...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."

Journal • Preclinical

Targeting estrogen metabolism in high-grade serous ovarian cancer shows promise to overcome platinum resistance. (PubMed, Biomed Pharmacother) - "In particular, targeting the activity of steroid sulfatase (STS) proves to be a promising therapeutic approach with potential efficacy in limiting estrogen-driven cell proliferation. Our study reveals potential prognostic markers as well as identifies novel therapeutic targets that show promise for overcoming resistance and improving treatment outcomes in HGSOC."

Journal • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor

An overview of the latest outlook of sulfamate derivatives as anticancer candidates (2020-2024). (PubMed, Arch Pharm (Weinheim)) - "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."

Journal • Review • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BRCA1

Targeting Chemoresistance in HGSOC: A Focus on Estrogen Metabolism (ISGE 2024) - "Objective To identify potential chemoresistance biomarkers in transcriptomic data from platinum-sensitive and -resistant HGSOC tissues.To better understand estrogen metabolism and expression of selected genes in HGSOC cell lines with different sensitivity to carboplatin. HSD17B14, NQO1, CYP1B1, SULT1E1, and ESR1 represent candidate prognostic biomarkers for HGSOC. EE2, EQ and STX64 are promising options for the targeted treatment of HGSOC, but further studies in preclinical models are needed to assess their true translational potential."

Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • CYP1A2 • CYP1B1 • ER • NQO1 • SULT1E1

ONESTX-1, A STEROID SULFATASE INHIBITOR, AS A NOVEL PHARMACOLOGICAL APPROACH TO TREAT ALZHEIMER'S DISEASE (ADPD 2024) - "Aims: ONESTX-1/STX64/irosustat is a small molecule that inhibits steroid sulfatase (STS) and showed to be active against Alzheimer and Parkinson in animal models... ONESTX-1 may act at different levels against the progression of Alzheimer's disease according to the preclinical data. The antiaging effect of ONESTX-1 at different levels has been shown to be a novel strategy to fight Alzheimer and Parkinson diseases. One of the downstream actions of ONESTX-1 administration was to induce cholinergic activity, which is impaired in Alzheimer's disease."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation • Movement Disorders • Oncology • Parkinson's Disease

Promising drug candidates for the treatment of polycystic ovary syndrome (PCOS) as alternatives to the classical medication metformin. (PubMed, Eur J Pharmacol) - "This study aimed to investigate the therapeutic potential of Irosustat (STX64), STX140, and compound 1G as new drug candidates for the treatment of letrozole-induced PCOS in female Wistar rats. In addition, Western blotting confirmed their promising effects on Akt, mTOR, and AMPK-α pathways. This study led to discovery of three promising drug candidates for management of PCOS as alternatives to metformin."

Journal • Polycystic Ovary Syndrome

Steroid sulfatase inhibitors and sulfated C19 steroids for proteotoxicity-related diseases: a patent spotlight. (PubMed, Pharm Pat Anal) - "One particular representative example is STX-64. Potential applications of the claims have been demonstrated in animal models of Parkinson's disease, Huntington's disease and Alzheimer's disease."

Journal • Alzheimer's Disease • CNS Disorders • Huntington's Disease • Movement Disorders • Parkinson's Disease

Host modulation therapy for improving the osseointegration of dental implants under bone healing-suppressed conditions: a preclinical rodent-model experiment. (PubMed, J Periodontal Implant Sci) - "Host modulation by increasing the CS level may enhance the osseointegration of dental implants placed under conditions of impaired bone healing."

Journal • Preclinical

Design, structure-activity relationships, and enzyme kinetic studies of tricyclic and tetracyclic coumarin-based sulfamates as steroid sulfatase inhibitors. (PubMed, Bioorg Chem) - "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 of 0.05 and 0.4 nM, and k/K ratios of 28.6 and 19.1 nMmin on human placenta STS, respectively."

Journal • Breast Cancer • Oncology • Solid Tumor

2-Methoxyestradiol-3,17-O,O-bis-sulfamate inhibits store-operated Ca entry in T lymphocytes and prevents experimental autoimmune encephalomyelitis. (PubMed, Biochim Biophys Acta Mol Cell Res) - "The likely underlying mechanism is inhibition of SOCE, as shown for its synthetic sulfamate ester analogue 2-ethyl-3-sulfamoyloxy-17β-cyanomethylestra-1,3,5(10)-triene (STX564). The STS inhibitory activity of STX140 is therefore not responsible for its activity in this model. Taken together, inhibition of SOCE by STX140 resulting in full antagonism of clinical symptoms in EAE in the Lewis rat, paired with the known excellent bioavailability and pharmaceutical profile of this drug, open potentially new therapeutic avenues for the treatment of MS."

Journal • CNS Disorders • Immunology • Multiple Sclerosis • Oncology • IFNG • IL17A • NFATC1

Novel Anti-Acanthamoebic Activities of Irosustat and STX140 and Their Nanoformulations. (PubMed, Antibiotics (Basel)) - "Irosustat and STX140 exhibited a biphasic release profile with almost 100% drug released after 48 h. Notably, Irosustat significantly inhibited A. castellanii viability and amoebae-mediated cytopathogenicity and inhibited the phenotypic transformation of amoebae cysts into the trophozoite form, however their nanoformulations depicted limited effects against amoebae but exhibited minimal cytotoxicity when tested against human cells using lactate dehydrogenase release assays. Accordingly, both compounds have potential for further studies, with the hope of discovering novel anti-Acanthamoeba compounds, and potentially developing targeted therapy against infections of the central nervous system."

Journal • CNS Disorders • Infectious Disease • Keratitis • Ocular Inflammation • Oncology • Ophthalmology

Dual aromatase-steroid sulfatase inhibitors (DASI's) for the treatment of breast cancer: a structure guided ligand based designing approach. (PubMed, J Biomol Struct Dyn) - "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."

Journal • Breast Cancer • Oncology • Solid Tumor

The Design, Structure-Activity, and kinetic studies of 3-Benzyl-5-oxa-1,2,3,4-Tetrahydro-2H-chromeno-(3,4-c)pyridin-8-yl sulfamates as Steroid sulfatase inhibitors. (PubMed, Bioorg Chem) - "We also used the docking model to illustrate the difference in STS inhibitory potency of compounds. Finally, the safety and anti-cancer activity of selected compounds 19m, 19v, and 19w were also studied, showing the results of low cytotoxicity on NHDF cell line and being more potent than irosustat on ZR-75-1 cell, which was a hormone-dependent cancer cell line with high STS expression."

Journal • Oncology

Inhibitor of Glucosinolate Sulfatases as a Potential Friendly Insecticide to Control Plutella xylostella. (PubMed, J Agric Food Chem) - "While fed on the Arabidopsis mutants deficient in myrosinase or glucosinolates, irosustat had no significant negative effect on P. xylostella. These findings reveal that the GSS inhibitor is a novel friendly insecticide to control P. xylostella utilizing the plant glucosinolate-myrosinase system and promote the development of insecticide-plant chemical defense combination strategies."

Journal

Development of Sulfamoylated 4-(1-Phenyl-1H-1,2,3-triazol-4-yl)phenol Derivatives as Potent Steroid Sulfatase Inhibitors for Efficient Treatment of Breast Cancer. (PubMed, J Med Chem) - "The most active compound, 5l, demonstrated an extraordinary STS inhibitory potency in MCF-7 cells with an IC value improved 5-fold compared to that of the reference Irosustat (0.21 vs 1.06 nM). The five most potent compounds were assessed in vivo in a 67NR mouse mammary gland cancer model, with 4b measured to induce up to 51% tumor growth inhibition at 50 mg/kg with no evidence of side effects and toxicity."

Journal • Breast Cancer • Oncology • Solid Tumor

Bisphenol A-sulfate conjugate disrupts AURKA transcription and cell cycle in BeWo cytotrophoblasts. (PubMed, Mol Cell Endocrinol) - "This growth inhibition was restored by treatment of the cells with an inhibitor of the organic anion-transporting peptides (OATPs) (bromosulphophthalein) or with a sulfatase (STS) inhibitor (STX64)...These results suggested that BPA-S triggers cell cycle arrest and inhibits proliferation of BeWo cytotrophoblasts by decreased AURKA, an effect that is mediated by the sulfate-sulfatase pathway. Overall, these findings provide insights into the reactivation of sulfated endocrine-disrupting chemicals and subsequent adverse effects."

Journal • AURKA

Blocking Estrogen Synthesis Leads to Different Hormonal Responses in Canine and Human Triple Negative Inflammatory Breast Cancer. (PubMed, Cancers (Basel)) - "Cell cultures and xenografts from IPC-366 and SUM149 were treated with different doses of letrozole (anti-aromatase) and STX-64 (anti-sulfatase), in order to observe their effectiveness in terms of cell proliferation, tumor progression, and the appearance of metastases and hormonal profiles. In conclusion, letrozole can be an effective treatment for canine and human inflammatory breast cancer. The knowledge of the hormonal profile of breast tumors reflects useful information on the effectiveness of different endocrine treatments."

Journal • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER

Steroid Sulfatase in the Mouse NIH-3T3 Fibroblast Cell Line: Characterization, and Downregulation by Glucocorticoids. (PubMed, Steroids) - "This activity was blocked by the STS inhibitors EMATE and STX-64, indicating authentic STS activity...The reduction in STS activity by dexamethasone in whole cells was reversed by the glucocorticoid receptor antagonist RU-486, indicating that glucocorticoid downregulation of STS activity is receptor mediated...This is consistent with the idea that cortisol inhibits STS in NIH-3T3 cells through a regulatory mechanism rather than by substrate inhibition. Our results could have important implications regarding local estrogen production by STS in fibroblasts, which are the most common connective tissue cells in the body, and on possible regulation of local estrogen levels by cortisol."

Journal • Preclinical

Steroid Sulphatase and Its Inhibitors: Past, Present, and Future. (PubMed, Molecules) - "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)...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."

Journal • Review • Colorectal Cancer • Endometriosis • Genito-urinary Cancer • Gynecology • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor

Steroid sulfatase inhibitors: the current landscape. (PubMed, Expert Opin Ther Pat) - "Irosustat is the most successful STS inhibitor drug candidate so far...They can be beneficial for treatment of hormone-dependent cancers and neurodegenerative disorders without significant estrogenic side effects. Moreover, dual-acting molecules (inhibitors of STS + another synergistic mechanism) can be therapeutically efficient."

Journal • Breast Cancer • CNS Disorders • Oncology • Solid Tumor

Anti-breast cancer potential of natural and synthetic coumarin derivatives. (PubMed, Curr Top Med Chem) - "Moreover, the coumarin-based Irosustat as the first-generation steroid sulfatase inhibitor in breast cancer is under clinical evaluations, revealing the potential of coumarin derivatives as novel anti-breast cancer agents. This review aims to describe the recent development of natural and synthetic coumarin derivatives with anti-breast cancer potential, covering the articles published from 2015 to 2020."

Journal • Breast Cancer • Oncology • Solid Tumor

2-Methoxyestradiol and its derivatives inhibit store-operated Ca entry in T cells: identification of a new and potent inhibitor. (PubMed, Biochim Biophys Acta Mol Cell Res) - "STX564 inhibits Ca entry via SOCE without affecting other ion channels and pumps involved in Ca signaling in T cells. Downstream effects such as cytokine expression and cell proliferation were also inhibited by both 2-methoxyestradiol and STX564, which has potential as a new chemical biology tool."

Journal