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

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.