Characterization of p38α autophosphorylation inhibitors that target the non-canonical activation pathway

TitleCharacterization of p38α autophosphorylation inhibitors that target the non-canonical activation pathway
Publication TypeJournal Article
Year of Publication2023
AuthorsGonzález, Lorena, Díaz Lucía, Pous Joan, Baginski Blazej, Duran-Corbera Anna, Scarpa Margherita, Brun-Heath Isabelle, Igea Ana, Martin-Malpartida Pau, Ruiz Lidia, Pallara Chiara, Esguerra Mauricio, Colizzi Francesco, Mayor-Ruiz Cristina, Biondi Ricardo M., Soliva Robert, Macias Maria J., Orozco Modesto, and Nebreda Angel R.
JournalNature Communications
Date Published06/2023
ISBN Number2041-1723

p38α is a versatile protein kinase that can control numerous processes and plays important roles in the cellular responses to stress. Dysregulation of p38α signaling has been linked to several diseases including inflammation, immune disorders and cancer, suggesting that targeting p38α could be therapeutically beneficial. Over the last two decades, numerous p38α 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 p38α modulation. Here, we report the in silico identification of compounds that we refer to as non-canonical p38α inhibitors (NC-p38i). By combining biochemical and structural analyses, we show that NC-p38i efficiently inhibit p38α autophosphorylation but weakly affect the activity of the canonical pathway. Our results demonstrate how the structural plasticity of p38α can be leveraged to develop therapeutic opportunities targeting a subset of the functions regulated by this pathway.

Short TitleNature Communications