Identification and Characterization of Novel Receptor-Interacting Serine/Threonine-Protein Kinase 2 Inhibitors Using Structural Similarity Analysis

J Pharmacol Exp Ther. 2018 May;365(2):354-367. doi: 10.1124/jpet.117.247163. Epub 2018 Mar 19.

Abstract

Receptor-interacting protein kinase 2 (RIP2 or RICK, herein referred to as RIPK2) is linked to the pathogen pathway that activates nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) and autophagic activation. Using molecular modeling (docking) and chemoinformatics analyses, we used the RIPK2/ponatinib crystal structure and searched in chemical databases for small molecules exerting binding interactions similar to those exerted by ponatinib. The identified RIPK2 inhibitors potently inhibited the proliferation of cancer cells by > 70% and also inhibited NFκB activity. More importantly, in vivo inhibition of intestinal and lung inflammation rodent models suggests effectiveness to resolve inflammation with low toxicity to the animals. Thus, our identified RIPK2 inhibitor may offer possible therapeutic control of inflammation in diseases such as inflammatory bowel disease, asthma, cystic fibrosis, primary sclerosing cholangitis, and pancreatitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Catalytic Domain
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colitis, Ulcerative / drug therapy
  • Drug Discovery*
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / pathology
  • Molecular Docking Simulation
  • NF-kappa B / metabolism
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / antagonists & inhibitors*
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / chemistry
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / metabolism

Substances

  • NF-kappa B
  • Protein Kinase Inhibitors
  • RIPK2 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinase 2