Biochemical and biophysical research communications · 2025
Identification of 8-(2-methyl phenyl)-9H-benzo[f]indeno[2,1-c]quinolin-9-one (C-5635020) as a novel and selective TGFβ RII kinase inhibitor for breast cancer therapy.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Al Shahrani Mesfer, Abohassan Mohammad, Alshahrani Mohammad, Gahtani Reem M, Rajagopalan Prasanna
Аннотация
OBJECTIVE AND SIGNIFICANCE: Transforming growth factor-beta (TGF-β) plays a pivotal role in breast development by modulating tissue composition during the developmental phase. The TGFβ type II receptor (TGFβ RII) is implicated in breast cancer and represents a valuable therapeutic target. Due to the off-target side effects of many existing TGFβI/TGFβ RII inhibitors, a more targeted approach to drug discovery is necessary. This study used computational modeling and molecular dynamics simulations to screen the ChemBridge small molecule library against TGFβ RII.
METHODS: This study employed high-throughput virtual screening, molecular dynamics simulations, and binding free energy calculations to identify potential inhibitors targeting TGF-β RII. MDA-MB 231 and MCF-7 breast cancer cells were used in anti-proliferative, tans-endothelial migration, and flow cytometric assays for in vitro validations.
RESULTS: We identified 8-(2-methylphenyl)-9H-benzo[f]indeno[2,1-c]quinolin-9-one (C-5635020) as a potent and selective inhibitor. Protein-ligand modeling analysis revealed that C-5635020 targets the kinase domain of TGFβ RII with superior binding affinities compared to the standard drug, staurosporine. Computational results suggest that C-5635020 selectively binds and inhibits TGFβ RII activity, thereby controlling cell proliferation in breast cancer. In vitro, experiments corroborated these predictions, where C-5635020 inhibited TGFβ RII and p-Smad 2/3 positive population in MDAMB-231 and MCF-7 cells. The compound dose-dependently inhibited cell proliferation, trans-endothelial migration, and increased apoptosis in both breast cancer cell lines.
CONCLUSION: The strong binding affinity, stability, and favorable thermodynamics of C-5635020 with established in vitro efficacy highlight its potential as a lead compound for further preclinical and clinical developments for breast cancer treatment.
METHODS: This study employed high-throughput virtual screening, molecular dynamics simulations, and binding free energy calculations to identify potential inhibitors targeting TGF-β RII. MDA-MB 231 and MCF-7 breast cancer cells were used in anti-proliferative, tans-endothelial migration, and flow cytometric assays for in vitro validations.
RESULTS: We identified 8-(2-methylphenyl)-9H-benzo[f]indeno[2,1-c]quinolin-9-one (C-5635020) as a potent and selective inhibitor. Protein-ligand modeling analysis revealed that C-5635020 targets the kinase domain of TGFβ RII with superior binding affinities compared to the standard drug, staurosporine. Computational results suggest that C-5635020 selectively binds and inhibits TGFβ RII activity, thereby controlling cell proliferation in breast cancer. In vitro, experiments corroborated these predictions, where C-5635020 inhibited TGFβ RII and p-Smad 2/3 positive population in MDAMB-231 and MCF-7 cells. The compound dose-dependently inhibited cell proliferation, trans-endothelial migration, and increased apoptosis in both breast cancer cell lines.
CONCLUSION: The strong binding affinity, stability, and favorable thermodynamics of C-5635020 with established in vitro efficacy highlight its potential as a lead compound for further preclinical and clinical developments for breast cancer treatment.