Discovery of antiproliferative and anti-FAK inhibitory activity of 1,2,4-triazole derivatives containing acetamido carboxylic acid skeleton
| Autor: | Pradipta Ghosh, Alaa M. Hayallah, Esam R. Ahmed, Muhamad Mustafa, Gamal El-Din A. Abuo-Rahma, Amer Ali Abd El-Hafeez, Dalia Abdelhamid |
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| Rok vydání: | 2021 |
| Předmět: |
Cell cycle checkpoint
Clinical Biochemistry Pharmaceutical Science Apoptosis Drug Screening Assays 01 natural sciences Biochemistry Anticancer activity Synthesis Drug Discovery Aminobenzoates Phosphorylation Cancer Tumor medicine.diagnostic_test Kinase Chemistry FAK inhibitors Pharmacology and Pharmaceutical Sciences Molecular Docking Simulation 5.1 Pharmaceuticals S Phase Cell Cycle Checkpoints Molecular Medicine Development of treatments and therapeutic interventions Docking study Protein Binding Medicinal & Biomolecular Chemistry Antineoplastic Agents Article Cell Line Focal adhesion Medicinal and Biomolecular Chemistry Rare Diseases Western blot Cell Line Tumor 4-triazoles medicine Humans Molecular Biology Protein kinase B IC50 Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Cell Proliferation 5-Pyridinyl-1 Binding Sites 010405 organic chemistry Organic Chemistry Antitumor Triazoles G1 Phase Cell Cycle Checkpoints 0104 chemical sciences 010404 medicinal & biomolecular chemistry Focal Adhesion Kinase 1 Cancer research Acetanilides Drug Screening Assays Antitumor |
| Zdroj: | Bioorg Med Chem Lett |
| Popis: | Small molecule inhibitors of the focal adhesion kinase are regarded as promising tools in our armamentarium for treating cancer. Here, we identified four 1,2,4-triazole derivatives that inhibit FAK kinase significantly and evaluated their therapeutic potential. Most tested compounds revealed potent antiproliferative activity in HepG2 and Hep3B liver cancer cells, in which 3c and 3d were the most potent (IC50 range; 2.88~4.83µM). Compound 3d possessed significant FAK inhibitory activity with IC50 value of 18.10nM better than the reference GSK-2256098 (IC50=22.14nM). The preliminary mechanism investigation by Western blot analysis showed that both 3c and 3d repressed FAK phosphorylation comparable to GSK-2256098 in HepG2 cells. As a result of FAK inhibition, 3c and 3d inhibited the pro-survival pathways by decreasing the phosphorylation levels of PI3K, Akt, JNK, and STAT3 proteins. This effect led to apoptosis induction and cell cycle arrest. Taken together, these results indicate that 3d could serve as a potent preclinical candidate for the treatment of cancers. |
| Databáze: | OpenAIRE |
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