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

Muhamad Mustafa; Amer Ali Abd El-Hafeez; Dalia Abdelhamid; Gajanan D Katkar; Yaser A Mostafa; Pradipta Ghosh; Alaa M Hayallah; Gamal El-Din A Abuo-Rahma

doi:10.1016/j.ejmech.2021.113569

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. Epub 2021 May 29.

Authors

Muhamad Mustafa¹, Amer Ali Abd El-Hafeez², Dalia Abdelhamid³, Gajanan D Katkar⁴, Yaser A Mostafa⁵, Pradipta Ghosh⁶, Alaa M Hayallah⁷, Gamal El-Din A Abuo-Rahma⁸

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.

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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Benzamides / chemistry
Benzamides / pharmacology
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Focal Adhesion Kinase 1 / antagonists & inhibitors*
Focal Adhesion Kinase 1 / metabolism
Histone Deacetylase 2 / antagonists & inhibitors*
Histone Deacetylase 2 / metabolism
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology*
Humans
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Triazoles / chemistry
Triazoles / pharmacology*
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Benzamides
Histone Deacetylase Inhibitors
Hydroxamic Acids
Protein Kinase Inhibitors
Triazoles
Focal Adhesion Kinase 1
PTK2 protein, human
HDAC2 protein, human
Histone Deacetylase 2

Abstract

MeSH terms

Substances

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