irosustat (BN 83495) / Ipsen - LARVOL DELTA

Arylsulfatase D promotes malignant phenotypes in glioblastoma cells and is linked to altered Hippo pathway phosphorylation. (PubMed, Front Oncol) - "These findings indicate that ARSD facilitates GBM malignant behavior and is linked to Merlin/LATS/YAP phosphorylation-related signaling. Irosustat showed preliminary antitumor activity in the xenograft model; however, because Irosustat is not an ARSD-specific inhibitor, the in vivo findings should not be interpreted as evidence of selective ARSD inhibition."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • YAP1

Design, Synthesis, and Biological Evaluation of Amide Derivatives of Coumarin-1,2,4-Thiadiazoles as Anticancer Agents. (PubMed, Chem Biodivers) - "The compounds exhibited good to moderate anticancer activity, with IC50 values ranging from 0.11 ± 0.029 to 9.12 ± 4.67 µM, whereas etoposide showed IC50 values ranging from 2.11 ± 0.024 to 3.11 ± 0.11 µM. Among the synthesized derivatives, 12a, 12b, 12c, and 12d displayed remarkable anticancer potency."

Journal • Oncology

EFFICACY OF STX64 LINKED TO STEROID SULFATASE INHIBITION IN THE R6/1 MODEL OF HUNTINGTON DISEASE (ADPD 2026) - "STX64 produced behavioral benefits in R6/1 mice consistent with clear inhibition of brain STS. These results support STX64 as a promising therapeutic candidate for Huntington's disease."

Clinical • Cognitive Disorders • Genetic Disorders • Huntington's Disease • Movement Disorders

STX64, A STEROID SULFATASE INHIBITOR, AS A NOVEL DISEASE-MODIFYING CANDIDATE FOR ALZHEIMER'S DISEASE THROUGH CHOLINERGIC MODULATION (ADPD 2026) - "STX64 enhances acetylcholine tone independently of AChE inhibition, rescues cognition in AD-relevant rodent models, and preserves cholinergic neurons in APP/PS1 mice. Cross-species convergence, together with validated biomarkers (brain STS inhibition, plasma steroid ratios), strongly supports the ongoing Phase IIa clinical trial in Alzheimer's disease."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • CHAT

Synthesis and Biological Evaluation of 3,5-Diaryl-Substituted 1,2,4-Oxadiazole Sulfamates as Potent Steroid Sulfatase Inhibitors. (PubMed, ACS Med Chem Lett) - "Molecular docking predicted high affinity (binding energies of up to -8.9 kcal·mol-1), often surpassing the reference Irosustat...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."

Journal • Breast Cancer • Oncology • Solid Tumor

Assessing endocrine resistance: monitoring circulating ESR1 mutations in Irosustat-treated ER positive breast cancer. (PubMed, Breast Cancer Res Treat) - "Analysis of serial plasma samples revealed highly dynamic ctESR1m during AI treatment and frequent detection of polyclonal ctESR1m 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."

Biomarker • Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER

Exploring the role of estrogens and steroid sulfatase inhibition in platinum resistance, proliferation, migration, and cell death in high-grade serous ovarian cancer cells. (PubMed, Biomed Pharmacother) - "These findings emphasize the role of estrogen signaling in modulating the chemotherapy response in HGSOC. Although STX64 may not consistently enhance carboplatin effects, its strong pro-apoptotic activity and selective efficacy in ER-positive cells, highlight its promise as a potential standalone or maintenance therapy."

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

Protective potential of Irosustat, STX140 and the sulfonate derivative 1G in counteracting cisplatin-induced renal and hepatic toxicities: An in vivo comparative study. (PubMed, Life Sci) - "This study evaluates the protective effects of irosustat, the steroidal bissulfamate STX140, and a sulfonate derivative (1G) against cisplatin-induced organ toxicity in a rat model, with silymarin and losartan as reference standards. These findings highlight irosustat, STX140, and 1G as promising candidates for attenuating cisplatin-induced organ toxicity without compromising its anticancer efficacy. However, further investigations are required to elucidate the precise molecular mechanisms, optimize synergistic dosing strategies, and assess long-term safety in preclinical models."

Journal • Preclinical • Oncology • TNFA

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