Discovery of 3-phenyl- and 3-N-piperidinyl-isothiazolo[4,3-b]pyridines as highly potent inhibitors of cyclin G-associated kinase

Eur J Med Chem. 2021 Mar 5:213:113158. doi: 10.1016/j.ejmech.2021.113158. Epub 2021 Jan 12.

Abstract

Structural modifications at position 3 of the isothiazolo[4,3-b]pyridine scaffold afforded a new series of cyclin G-associated kinase (GAK) inhibitors. It was shown that the insertion of a carboxamide residue at position 3 of a phenyl or piperidinyl moiety generated potent GAK inhibitors with IC50 values in a low nanomolar range. This potent GAK binding affinity was rationalized by molecular modelling demonstrating that the carboxamide moiety engages in an extra hydrogen bond with GAK. Moreover, this new series of compounds was also endowed with antiviral activity against dengue virus, highlighting the potential utility of GAK as a target for the development of antiviral drugs.

Keywords: Antiviral agents; Cyclin G-associated kinase; Dengue virus; Isothiazolo[4,3-b]pyridine; Kinase inhibitor.

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dengue Virus / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Structure-Activity Relationship

Substances

  • Antiviral Agents
  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • GAK protein, human
  • Protein Serine-Threonine Kinases