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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
From a medicinal chemistry perspective, irosustat is distinctive in its relatively small size and simplicity which leads to good oral availability. Structure-Activity Relationship (SAR) studies showed that enlargement of the heptene ring from 7–11 atoms increased inhibitory potency, and the best of these ring-expanded analogues had in vitro IC50 values in the 0.015–0.025 nm range in JEG-3 cells which are sensitive to sulfatase inhibitors. Other chemical modifications such as N,N-dimethylation of the sulfamate group, relocating it to another position or adding flanking substituents were found to significantly weaken or abolish activity. Similarly, members of related series of quinoline and quinolin-2(1H)-one derivatives of irosustat were less active or inactive.
New potent steroid sulphatase inhibitors based on 6-(1-phenyl-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate derivatives
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Olga Ciupak, Mateusz Daśko, Karol Biernacki, Janusz Rachon, Maciej Masłyk, Konrad Kubiński, Aleksandra Martyna, Sebastian Demkowicz
Nowadays, STS has been considered as an attractive molecular target for the development of hormone-dependent cancer therapies, and therefore, the synthesis of new, efficient, selective STS inhibitors is of particular importance for modern medicinal chemistry. Recently, there has been intensive research towards finding novel STS inhibitors. Scientists have developed, both, steroidal and non-steroidal compounds containing various functional groups (e.g. sulphamate and phosphorus moieties)13. For example, one of the most promising drug candidate based on a sulphamoylated coumarin core is Irosustat (also known as 667-COUMATE or STX64). Irosustat is in clinical trials (phase II clinical studies) and exhibits quite good results towards treating hormone-dependent breast cancer (without having in vivo and in vitro oestrogenic properties)14–20. Although Irosustat showed very promising clinical effects in the treatment of hormone-dependent tumours, in relation to endometrium (where occurs high STS activity) Irosustat did not demonstrate activity sufficient for future commercial development21. For this reason, the search for more effective STS inhibitors is still ongoing.
Steroid sulfatase inhibitors: the current landscape
Published in Expert Opinion on Therapeutic Patents, 2021
Hanan S. Anbar, Zahraa Isa, Jana J. Elounais, Mariam A. Jameel, Joudi H. Zib, Aya M. Samer, Aya F. Jawad, Mohammed I. El-Gamal
Recent patents about therapeutic uses of irosustat have been applied or registered. One patent has reported potential therapeutic value of irosustat for treatment or prevention of neurodegenerative disorders[91]. It was also reported as a potential agent for aging treatment [92,93]. In addition, a Chinese group report that irosustat can be used for treatment of eimeria tenella in veterinary use[94]. Irosustat is currently under consideration in clinical trial for treatment of hormone-dependent breast, endometrial, and prostate cancers[95].
Recent progress in the development of steroid sulphatase inhibitors – examples of the novel and most promising compounds from the last decade
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Mateusz Daśko, Sebastian Demkowicz, Karol Biernacki, Olga Ciupak, Witold Kozak, Maciej Masłyk, Janusz Rachon
An important class of compounds that proved to be promising mimics of known steroidal STS inhibitors are sulphamoylated coumarin derivatives. It has been noticed that these analogues exhibited high inhibitory potency against STS and fewer adverse effects, such as much weaker oestrogenic properties than EMATE46. Similar to EMATE, the sulphamoylated coumarin analogues, e.g. 4-methylcoumarin-7-O-sulphamate (also known as COUMATE) 15 (Figure 5), are classified as irreversible inhibitors that act in a time- and concentration-dependent manner. COUMATE exhibited good activity with an IC50 value of 380 nM (when evaluated against placental microsomes)47. Its modification through the introduction of an additional aliphatic ring gave rise to a wide range of tricyclic coumarin derivatives that mimicked the ABC rings of the natural substrate and demonstrated significantly higher inhibitory effects than COUMATE. For example, one of the most promising drug candidates based on a sulphamoylated coumarin core, Irosustat16 (Figure 5), exhibited very potent activity towards STS (IC50 value of 8 nM) without having in vitro and in vivo oestrogenic properties48,49. Woo et al.50 published a key paper dedicated to the SAR studies for this first-in-class clinical STS inhibitor. The compound was characterised by favourable bioavailability (however, the bioavailability decreases with increasing doses)51, and was orally active and well-tolerated in patients52. It has reached clinical trials, and its high therapeutic potential has been proven in several clinical studies53,54. A combination therapy of Irosustat with a first-line aromatase inhibitor (phase II clinical studies) in patients with advanced ER-positive breast cancer resulted in clinical benefits with an acceptable safety profile55,56. Furthermore, Irosustat has recently shown clinical advantages in early breast cancer57 and ER-positive advanced endometrial cancer treatments58.