Identification of a novel series of azabenzimidazole-derived inhibitors of spleen tyrosine kinase

Bioorg Med Chem Lett. 2020 Sep 15;30(18):127393. doi: 10.1016/j.bmcl.2020.127393. Epub 2020 Jul 10.

Abstract

Spleen Tyrosine Kinase (SYK) is a well-studied enzyme with therapeutic applications in oncology and autoimmune diseases. We identified an azabenzimidazole (ABI) series of SYK inhibitors by mining activity data of 86,000 compounds from legacy biochemical assays with SYK and other homologous kinases as target enzymes. A structure-based design and hybridization approach was then used to improve the potency and kinase selectivity of the hits. Lead compound 23 from this novel ABI series has a SYK IC50 = 0.21 nM in a biochemical assay and inhibits growth of SUDHL-4 cells at a GI50 = 210 nM.

Keywords: ABI; Kinase selectivity; SYK; Structure-based drug design.

MeSH terms

  • Amino Acid Sequence
  • Autoimmune Diseases / drug therapy*
  • Aza Compounds / chemistry*
  • Aza Compounds / pharmacology
  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacology
  • Cell Line
  • Cell Proliferation / drug effects
  • Drug Design
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Substrate Specificity
  • Syk Kinase / antagonists & inhibitors*

Substances

  • Aza Compounds
  • Benzimidazoles
  • Protein Kinase Inhibitors
  • benzimidazole
  • Syk Kinase