Development of a potent and selective chemical probe for the pleiotropic kinase CK2

  • Cell Chem Biol. 2021 Apr 15;28(4):546-558.e10. doi: 10.1016/j.chembiol.2020.12.013.
Carrow I Wells  1 ,  David H Drewry  1 ,  Julie E Pickett  1 ,  Amelie Tjaden  2 ,  Andreas Krämer  2 ,  Susanne Müller  2 ,  Laszlo Gyenis  3 ,  Daniel Menyhart  3 ,  David W Litchfield  4 ,  Stefan Knapp  2 ,  Alison D Axtman  5
Affiliations
  • 1. Structural Genomics Consortium (SGC), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill (UNC-CH), Chapel Hill, NC 27599, USA; Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, UNC-CH, Chapel Hill, NC 27599, USA.
  • 2. Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany; Structural Genomics Consortium, Buchman Institute for Life Sciences, Johann Wolfgang Goethe-University, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
  • 3. Department of Biochemistry, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.
  • 4. Department of Biochemistry, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada; Department of Oncology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.
  • 5. Structural Genomics Consortium (SGC), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill (UNC-CH), Chapel Hill, NC 27599, USA; Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, UNC-CH, Chapel Hill, NC 27599, USA. Electronic address: [email protected].
PMID: 33484635 DOI: 10.1016/j.chembiol.2020.12.013
Abstract

Building on the pyrazolopyrimidine CK2 (Casein Kinase 2) inhibitor scaffold, we designed a small targeted library. Through comprehensive evaluation of inhibitor selectivity, we identified inhibitor 24 (SGC-CK2-1) as a highly potent and cell-active CK2 Chemical probe with exclusive selectivity for both human CK2 isoforms. Remarkably, despite years of research pointing to CK2 as a key driver in Cancer, our chemical probe did not elicit a broad antiproliferative phenotype in >90% of >140 cell lines when tested in dose-response. While many publications have reported CK2 functions, CK2 biology is complex and an available high-quality chemical tool such as SGC-CK2-1 will be indispensable in deciphering the relationships between CK2 function and phenotypes.

Keywords
CK2; IDG; cancer; casein kinase 2; chemical probe; crystal structure; kinase; nanoBRET; proliferation; small molecule.
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