Characterization of p38 alpha autophosphorylation inhibitors that target the non-canonical activation pathway

p38 alpha is a versatile protein kinase that can control numerous processes and plays important roles in the cellular responses to stress. Dysregulation of p38 alpha signaling has been linked to several diseases including inflammation, immune disorders and cancer, suggesting that targeting p38 alpha could be therapeutically beneficial. Over the last two decades, numerous p38 alpha inhibitors have been developed, which showed promising effects in pre-clinical studies but results from clinical trials have been disappointing, fueling the interest in the generation of alternative mechanisms of p38 alpha modulation. Here, we report the in silico identification of compounds that we refer to as non-canonical p38 alpha inhibitors (NC-p38i). By combining biochemical and structural analyses, we show that NC-p38i efficiently inhibit p38 alpha autophosphorylation but weakly affect the activity of the canonical pathway. Our results demonstrate how the structural plasticity of p38 alpha can be leveraged to develop therapeutic opportunities targeting a subset of the functions regulated by this pathway. The p38 alpha protein kinase is an attractive druggable target for many human diseases. Here, the authors show how the structural plasticity of p38 alpha can be leveraged to selectively inhibit a subset of the functions regulated by this kinase and aid in the development of therapeutic compounds.

Automated summary

p38 alpha is a versatile protein kinase that plays important roles in cellular stress responses. Dysregulation of p38 alpha signaling is linked to several diseases, making it a potential therapeutic target.