Development of a Selective Dual Discoidin Domain Receptor (DDR)/p38 Kinase Chemical Probe

J Med Chem. 2021 Sep 23;64(18):13451-13474. doi: 10.1021/acs.jmedchem.1c00868. Epub 2021 Sep 10.


Discoidin domain receptors 1 and 2 (DDR1/2) play a central role in fibrotic disorders, such as renal and pulmonary fibrosis, atherosclerosis, and various forms of cancer. Potent and selective inhibitors, so-called chemical probe compounds, have been developed to study DDR1/2 kinase signaling. However, these inhibitors showed undesired activity on other kinases such as the tyrosine protein kinase receptor TIE or tropomyosin receptor kinases, which are related to angiogenesis and neuronal toxicity. In this study, we optimized our recently published p38 mitogen-activated protein kinase inhibitor 7 toward a potent and cell-active dual DDR/p38 chemical probe and developed a structurally related negative control. The structure-guided design approach used provided insights into the P-loop folding process of p38 and how targeting of non-conserved amino acids modulates inhibitor selectivity. The developed and comprehensively characterized DDR/p38 probe, 30 (SR-302), is a valuable tool for studying the role of DDR kinase in normal physiology and in disease development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site
  • Animals
  • Benzamides / chemical synthesis
  • Benzamides / metabolism
  • Benzamides / pharmacology*
  • Cell Line, Tumor
  • Discoidin Domain Receptor 1 / chemistry
  • Discoidin Domain Receptor 1 / metabolism*
  • Discoidin Domain Receptor 2 / chemistry
  • Discoidin Domain Receptor 2 / metabolism*
  • Dogs
  • HEK293 Cells
  • Humans
  • Madin Darby Canine Kidney Cells
  • Microsomes, Liver / metabolism
  • Protein Binding
  • Sulfonamides / chemical synthesis
  • Sulfonamides / metabolism
  • Sulfonamides / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / chemistry
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Benzamides
  • Sulfonamides
  • DDR1 protein, human
  • DDR2 protein, human
  • Discoidin Domain Receptor 1
  • Discoidin Domain Receptor 2
  • p38 Mitogen-Activated Protein Kinases