2. Academic Validation
  3. A first-in-class anticancer dual HDAC2/FAK inhibitors bearing hydroxamates/benzamides capped by pyridinyl-1,2,4-triazoles

A first-in-class anticancer dual HDAC2/FAK inhibitors bearing hydroxamates/benzamides capped by pyridinyl-1,2,4-triazoles

  • Eur J Med Chem. 2021 Oct 15:222:113569. doi: 10.1016/j.ejmech.2021.113569.
Muhamad Mustafa 1,  Amer Ali Abd El-Hafeez 2,  Dalia Abdelhamid 3,  Gajanan D Katkar 4,  Yaser A Mostafa 5,  Pradipta Ghosh 6,  Alaa M Hayallah 7,  Gamal El-Din A Abuo-Rahma 8
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Deraya University, Minia, Egypt.
  • 2 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. Electronic address: aam002@health.ucsd.edu.
  • 3 Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt.
  • 4 Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • 5 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, 71526, 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; Moores 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.
  • 8 Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Deraya University, Minia, Egypt. Electronic address: gamal.aborahma@mu.edu.eg.
PMID: 34111829 DOI: 10.1016/j.ejmech.2021.113569
Abstract

Novel 5-pyridinyl-1,2,4-triazoles were designed as dual inhibitors of histone deacetylase 2 (HDAC2) and focal adhesion kinase (FAK). Compounds 5d, 6a, 7c, and 11c were determined as potential inhibitors of both HDAC2 (IC50 = 0.09-1.40 μM) and FAK (IC50 = 12.59-36.11 nM); 6a revealed the highest activity with IC50 values of 0.09 μM and 12.59 nM for HDAC2 and FAK, respectively. Compound 6a was superior to reference drugs vorinostat and valproic acid in its ability to inhibit growth/proliferation of A-498 and Caki-1 renal Cancer cells. Further investigation proved that 6a strongly arrests the cell cycle at the G2/M phase and triggers Apoptosis in both A-498 and Caki-1 cells. Moreover, the enhanced Akt activity that is observed upon chronic application of HDAC inhibitors was effectively suppressed by the dual HDAC2/FAK Inhibitor. Finally, the high potency and selectivity of 6a towards HDAC2 and FAK proteins were rationalized by molecular docking. Taken together, these findings highlight the potential of 6a as a promising dual-acting HDAC2/FAK Inhibitor that could benefit from further optimization.

Keywords

1,2,4-Triazoles; Anticancer; FAK; HDAC2; Molecular docking.

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