Identification, structure modification, and characterization of potential small-molecule SGK3 inhibitors with novel scaffolds

Acta Pharmacol Sin. 2018 Dec;39(12):1902-1912. doi: 10.1038/s41401-018-0087-6. Epub 2018 Jul 23.

Abstract

The serum and glucocorticoid-regulated kinase (SGK) family has been implicated in the regulation of many cellular processes downstream of the PI3K pathway. It plays a crucial role in PI3K-mediated tumorigenesis, making it a potential therapeutic target for cancer. SGK family consists of three isoforms (SGK1, SGK2, and SGK3), which have high sequence homology in the kinase domain and similar substrate specificity with the AKT family. In order to identify novel compounds capable of inhibiting SGK3 activity, a high-throughput screening campaign against 50,400 small molecules was conducted using a fluorescence-based kinase assay that has a Z' factor above 0.5. It identified 15 hits (including nitrogen-containing aromatic, flavone, hydrazone, and naphthalene derivatives) with IC50 values in the low micromolar to sub-micromolar range. Four compounds with a similar scaffold (i.e., a hydrazone core) were selected for structural modification and 18 derivatives were synthesized. Molecular modeling was then used to investigate the structure-activity relationship (SAR) and potential protein-ligand interactions. As a result, a series of SGK inhibitors that are active against both SGK1 and SGK3 were developed and important functional groups that control their inhibitory activity identified.

Keywords: SGK3; high-throughput screening; inhibitors; molecular modeling; serum and glucocorticoid-regulated kinase.

MeSH terms

  • Catalytic Domain
  • Cell Line, Tumor
  • Enzyme Assays
  • Humans
  • Immediate-Early Proteins / antagonists & inhibitors*
  • Immediate-Early Proteins / chemistry
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / chemistry
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Immediate-Early Proteins
  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • Protein-Serine-Threonine Kinases
  • SGK3 protein, human
  • serum-glucocorticoid regulated kinase