2. Academic Validation
  3. Discovery of a Potent and Selective Naphthyridine-Based Chemical Probe for Casein Kinase 2

Discovery of a Potent and Selective Naphthyridine-Based Chemical Probe for Casein Kinase 2

  • ACS Med Chem Lett. 2023 Mar 14;14(4):432-441. doi: 10.1021/acsmedchemlett.2c00530.
Zachary W Davis-Gilbert 1,  Andreas Krämer 2 3 4,  James E Dunford 5,  Stefanie Howell 1,  Filiz Senbabaoglu 5,  Carrow I Wells 1,  Frances M Bashore 1,  Tammy M Havener 1,  Jeffery L Smith 1,  Mohammad A Hossain 1,  Udo Oppermann 5 6,  David H Drewry 1 7,  Alison D Axtman 1
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 2 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strabe 9, Frankfurt 60438, Germany.
  • 3 Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe University Frankfurt, Max-von-Laue-Strabe 15, Frankfurt 60438, Germany.
  • 4 Frankfurt Cancer Institute, Paul-Ehrlich-Straße 42-44, Frankfurt 60596, Germany.
  • 5 Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, United Kingdom.
  • 6 Oxford Translational Myeloma Centre, University of Oxford, Oxford OX3 7LD, United Kingdom.
  • 7 UNC Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
PMID: 37077385 DOI: 10.1021/acsmedchemlett.2c00530
Abstract

Naphthyridine-based inhibitors were synthesized to yield a potent and cell-active inhibitor of Casein Kinase 2 (CK2). Compound 2 selectively inhibits CK2α and CK2α' when profiled broadly, thereby making it an exquisitely selective chemical probe for CK2. A negative control that is structurally related but lacks a key hinge-binding nitrogen (7) was designed on the basis of structural studies. Compound 7 does not bind CK2α or CK2α' in cells and demonstrates excellent kinome-wide selectivity. Differential Anticancer activity was observed when compound 2 was profiled alongside a structurally distinct CK2 Chemical probe: SGC-CK2-1. This naphthyridine-based chemical probe (2) represents one of the best available small molecule tools with which to interrogate biology mediated by CK2.

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