2. Academic Validation
  3. Discovery of antiproliferative and anti-FAK inhibitory activity of 1,2,4-triazole derivatives containing acetamido carboxylic acid skeleton

Discovery of antiproliferative and anti-FAK inhibitory activity of 1,2,4-triazole derivatives containing acetamido carboxylic acid skeleton

  • Bioorg Med Chem Lett. 2021 May 15:40:127965. doi: 10.1016/j.bmcl.2021.127965.
Muhamad Mustafa 1,  Gamal El-Din A Abuo-Rahma 2,  Amer Ali Abd El-Hafeez 3,  Esam R Ahmed 4,  Dalia Abdelhamid 5,  Pradipta Ghosh 6,  Alaa M Hayallah 7
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Deraya University, Minia, Egypt; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
  • 2 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Deraya University, Minia, Egypt; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt. Electronic address: [email protected].
  • 3 Pharmacology and Experimental Oncology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • 4 VACSERA, Cairo, Egypt.
  • 5 Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
  • 6 Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Department of Medicine, University of California San Diego, La Jolla, CA, USA; Rebecca and John Moore Comprehensive Cancer Center, University of California San Diego, La Jolla, CA, USA; Veterans Affairs Medical Center, La Jolla, CA, USA.
  • 7 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Deraya University, Minia, Egypt; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, 71526, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Sphinx University, New Assiut, Egypt.
PMID: 33744442 DOI: 10.1016/j.bmcl.2021.127965
Abstract

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 ~ 4.83 µM). Compound 3d possessed significant FAK inhibitory activity with IC50 value of 18.10 nM better than the reference GSK-2256098 (IC50 = 22.14 nM). 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.

Keywords

5-Pyridinyl-1,2,4-triazoles; Anticancer activity; Docking study; FAK inhibitors; Synthesis.

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