2. Academic Validation
  3. 2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 2. Structure-Based Optimization and Investigation of Effects Specific to the Allosteric Mode of Action

2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 2. Structure-Based Optimization and Investigation of Effects Specific to the Allosteric Mode of Action

  • J Med Chem. 2019 Feb 28;62(4):1817-1836. doi: 10.1021/acs.jmedchem.8b01765.
Benoît Bestgen 1 2 3 4 5,  Irina Kufareva 6,  Weiguang Seetoh 7,  Chris Abell 7,  Rolf W Hartmann 8,  Ruben Abagyan 6,  Marc Le Borgne 1,  Odile Filhol 3 4 5,  Claude Cochet 3 4 5,  Thierry Lomberget 1,  Matthias Engel 2
Affiliations

Affiliations

  • 1 Université de Lyon, Université Lyon 1, Faculté de Pharmacie, ISPB, EA 4446 Bioactive Molecules and Medicinal Chemistry, SFR Santé Lyon-Est CNRS UMS3453, INSERM US7, 69373 Lyon Cedex 8, France.
  • 2 Pharmaceutical and Medicinal Chemistry , Saarland University , Campus C2.3, 66123 Saarbrücken , Germany.
  • 3 Institut National de la Santé et de la Recherche Médicale , U1036, 38000 Grenoble , France.
  • 4 Commissariat à l'Energie Atomique, Institute of Life Sciences Research and Technologies, Biology of Cancer and Infection, 38000 Grenoble , France.
  • 5 Unité Mixte de Recherche-S1036 , University of Grenoble Alpes , 38000 Grenoble , France.
  • 6 Skaggs School of Pharmacy and Pharmaceutical Sciences , University of California, San Diego , La Jolla , California 92093 , United States.
  • 7 Department of Chemistry , University of Cambridge , Lensfield Road , Cambridge CB2 1EW , U.K.
  • 8 Department of Drug Design and Optimization , Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Campus C2.3, 66123 Saarbrücken , Germany.
PMID: 30689946 DOI: 10.1021/acs.jmedchem.8b01765
Abstract

Protein CK2 has gained much interest as an Anticancer drug target in the past decade. We had previously described the identification of a new allosteric site on the catalytic α-subunit, along with first small molecule ligands based on the 4-(4-phenylthiazol-2-ylamino)benzoic acid scaffold. In the present work, structure optimizations guided by a binding model led to the identification of the lead compound 2-hydroxy-4-((4-(naphthalen-2-yl)thiazol-2-yl)amino)benzoic acid (27), showing a submicromolar potency against purified CK2α (IC50 = 0.6 μM). Furthermore, 27 induced Apoptosis and cell death in 786-O renal cell carcinoma cells (EC50 = 5 μM) and inhibited STAT3 activation even more potently than the ATP-competitive drug candidate CX-4945 (EC50 of 1.6 μM vs 5.3 μM). Notably, the potencies of our allosteric ligands to inhibit CK2 varied depending on the individual substrate. Altogether, the novel allosteric pocket was proved a druggable site, offering an excellent perspective to develop efficient and selective allosteric CK2 inhibitors.

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