2. Academic Validation
  3. Discovery of a novel, selective CK2 inhibitor class with an unusual basic scaffold

Discovery of a novel, selective CK2 inhibitor class with an unusual basic scaffold

  • Eur J Med Chem. 2025 Jan 15:282:117048. doi: 10.1016/j.ejmech.2024.117048.
Hend Khalifa 1,  Ahmed K ElHady 2,  Ting Liu 3,  Walid A M Elgaher 4,  Odile Filhol-Cochet 5,  Claude Cochet 5,  Ashraf H Abadi 1,  Mostafa M Hamed 4,  Mohammad Abdel-Halim 6,  Matthias Engel 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835, Cairo, Egypt.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835, Cairo, Egypt; School of Life and Medical Sciences, University of Hertfordshire Hosted By Global Academic Foundation, New Administrative Capital, Cairo, Egypt.
  • 3 Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, 66123, Saarbrücken, Germany.
  • 4 Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus, 66123, Saarbrücken, Germany.
  • 5 University Grenoble Alpes, INSERM 1292, CEA, UMR Biosante, 38000, Grenoble, France.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835, Cairo, Egypt. Electronic address: mohammad.abdel-halim@guc.edu.eg.
  • 7 Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, 66123, Saarbrücken, Germany. Electronic address: ma.engel@mx.uni-saarland.de.
PMID: 39566243 DOI: 10.1016/j.ejmech.2024.117048
Abstract

CK2 is a Ser/Thr-protein kinase playing a crucial role in promoting cell growth and survival, hence it is considered a promising target for anti-cancer drugs. However, many previously reported CK2 inhibitors lack selectivity. In search of novel scaffolds for selective CK2 inhibition, we identified a dihydropyrido-thieno[2,3-d]pyrimidine derivative displaying submicromolar inhibitory activity against CK2α. This scaffold captured our interest because of the basic secondary amine, a rather unusual motif for CK2 inhibitors. Our optimization strategy comprised the incorporation of a 4-piperazinyl moiety as a linker group and introduction of varying substituents on the pendant phenyl ring. All resulting compounds exhibited potent CK2α inhibition, with IC50 values in the nanomolar range. Compound 10b demonstrated the most balanced activity profile with a cell-free IC50 value of 36.7 nM and a notable cellular activity with a GI50 of 7.3 μM and 7.5 μM against 786-O renal cell carcinoma and U937 lymphoma cells, respectively. 10b displayed excellent selectivity when screened against a challenging kinase selectivity profiling panel. Moreover, 10b inhibited CK2 in the cells, albeit less potently than CX-4945, but induced cell death more strongly than CX-4945. Altogether, we have identified a novel CK2 inhibitory scaffold with drug-like physicochemical properties in a favorable basic PKA range.

Keywords

ATP-Competitive inhibition; CK2; Kinase inhibitors; Thienopyrimidines.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-168707
    CK2 Inhibitor
    CDK