2. Academic Validation
  3. Development of a potent and selective chemical probe for the pleiotropic kinase CK2

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

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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