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Design and synthesis of phosphoryl-substituted steroidal pyridazines (Pho-STPYRs) as potent estrogen receptor alpha inhibitors: targeted treatment of hormone-dependent breast cancer cellsстатья Исследовательская статья
- Авторы: Volkova Yulia A., Scherbakov Alexander M., Dzichenka Yaraslau U., Komkov Alexander V., Bogdanov Fedor B., Salnikova Diana I., Dmitrenok Andrey S., Sachanka Antos, Sorokin Danila V., Zavarzin Igor V.
- Журнал: RSC Medicinal Chemistry
- Год издания: 2024
- Издательство: Royal Society of Chemistry
- Местоположение издательства: United Kingdom
- DOI: 10.1039/d4md00153b
- Аннотация: Estrogen receptor alpha (ERα) is an important target for the discovery of new therapeutic drugs against hormone-dependent breast cancer. A series of phosphoryl-substituted steroidal pyridazines (Pho-STPYRs) were synthesized and biologically evaluated as potent ERα inhibitors. Pho-STPYR showed cytotoxicity against breast cancer cells with IC50 values of 5.9 µM and higher. Pho-STPYRs 33 and 34 [IC50(MCF7) = 6.5 and 5.9 µM, respectively] were found to block the expression of ERα, the main driver of breast cancer growth, and modulate the ERK, cyclin D1, and CDK4 pathways. Compound 34 showed selectivity, anti-estrogenic potency and high antiproliferative efficacy in combination with AKT inhibitor. Molecular docking was used to more accurately define the binding mode of lead compounds 33 and 34 to ERα. The selectivity analysis showed that lead compounds 33 and 34 produce no effects on cytochromes P450, including CYP7A1, CYP7B1, CYP17A1, CYP19A1, and CYP21A2. In a word, Pho-STPYRs 33 and 34 are promising ERα inhibitors for the treatment of hormone-dependent breast cancer.
- Добавил в систему: Сальникова Диана Игоревна