Design, synthesis, and SAR study of highly potent, selective, irreversible covalent JAK3 inhibitors

Mol Divers. 2018 May;22(2):343-358. doi: 10.1007/s11030-017-9803-2. Epub 2018 Feb 6.

Abstract

Here, we report the design and synthesis of pyrimidinyl heterocyclic compounds containing terminal electrophiles as irreversible covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Investigation of the structure-activity relationship utilizing kinase assays resulted in the identification of potent and selective JAK3 inhibitors such as T1, T8, T15, T22, and T29. Among them, T29 was verified as a promising JAK3 irreversible inhibitor that possessed the best bioactivity and selectivity against JAKs and kinases containing a cysteine in the residue analogous to Cys909 in JAK3, suggesting that covalent modification of this Cys residue allowed the identification of a highly selective JAK3 inhibitor. Moreover, T29 also displayed a significant anti-inflammatory effect in ICR mice through the inhibition of increased paw thickness, which is worth further optimization to increase its potency and medicinal properties.

Keywords: Covalent inhibitor; Docking; JAK3; Selectivity; Structure–activity relationship (SAR).

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / metabolism
  • Anti-Inflammatory Agents / pharmacology*
  • Chemistry Techniques, Synthetic
  • Drug Design*
  • Janus Kinase 3 / antagonists & inhibitors*
  • Janus Kinase 3 / chemistry
  • Janus Kinase 3 / metabolism
  • Mice
  • Mice, Inbred ICR
  • Models, Molecular
  • Protein Domains
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents
  • Protein Kinase Inhibitors
  • Janus Kinase 3