irosustat (BN 83495)

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.

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.

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.

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.

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.

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.