2. Academic Validation
  3. Structure-Based Development of Isoform-Selective Inhibitors of Casein Kinase 1ε vs Casein Kinase 1δ

Structure-Based Development of Isoform-Selective Inhibitors of Casein Kinase 1ε vs Casein Kinase 1δ

  • J Med Chem. 2023 Jun 8;66(11):7162-7178. doi: 10.1021/acs.jmedchem.2c01180.
Jun Yong Choi 1 2 3,  Yoshihiko Noguchi 1,  James M Alburger 1,  Simon Bayle 4,  Eugene Chung 2,  Wayne Grant 5,  Apirat Chaikuad 6 7,  Stefan Knapp 6 7,  Derek R Duckett 4,  William R Roush 1
Affiliations

Affiliations

  • 1 Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States.
  • 2 Department of Chemistry and Biochemistry, Queens College, Queens, New York 11367, United States.
  • 3 Ph.D. Programs in Chemistry and Biochemistry, The Graduate Center of the City University of New York, New York, New York 10016, United States.
  • 4 Department of Drug Discovery, Moffitt Cancer Center, Tampa, Florida 33612, United States.
  • 5 Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States.
  • 6 Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt am Main 60438, Germany.
  • 7 Structural Genomics Consortium, BMLS, Goethe University, Frankfurt am Main 60438, Germany.
PMID: 37204207 DOI: 10.1021/acs.jmedchem.2c01180
Abstract

Specific inhibition of a single kinase isoform is a challenging task due to the highly conserved nature of ATP-binding sites. Casein Kinase 1 (CK1) δ and ε share 97% sequence identity in their catalytic domains. From a comparison of the X-ray crystal structures of CK1δ and CK1ε, we developed a potent and highly CK1ε-isoform-selective inhibitor (SR-4133). The X-ray co-crystal structure of the CK1δ-SR-4133 complex reveals that the electrostatic surface between the naphthyl unit of SR-4133 and CK1δ is mismatched, destabilizing the interaction of SR-4133 with CK1δ. Conversely, the hydrophobic surface area resulting from the Asp-Phe-Gly motif (DFG)-out conformation of CK1ε stabilizes the binding of SR-4133 in the ATP-binding pocket of CK1ε, leading to the selective inhibition of CK1ε. The potent CK1ε-selective agents display nanomolar growth inhibition of bladder Cancer cells and inhibit the phosphorylation of 4E-BP1 in T24 cells, which is a direct downstream effector of CK1ε.

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