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

Lorena González, Lucía Díaz, Joan Pous, Blazej Baginski, Anna Duran-Corbera, Margherita Scarpa, Isabelle Brun-Heath, Ana Igea, Pau Martin-Malpartida, Lidia Ruiz, Chiara Pallara, Mauricio Esguerra, Francesco Colizzi, Cristina Mayor-Ruiz, Ricardo M. Biondi, Robert Soliva, Maria J. Macias (), Modesto Orozco () and Angel R. Nebreda ()
Additional contact information
Lorena González: The Barcelona Institute of Science and Technology
Lucía Díaz: Nostrum Biodiscovery
Joan Pous: The Barcelona Institute of Science and Technology
Blazej Baginski: The Barcelona Institute of Science and Technology
Anna Duran-Corbera: The Barcelona Institute of Science and Technology
Margherita Scarpa: The Barcelona Institute of Science and Technology
Isabelle Brun-Heath: The Barcelona Institute of Science and Technology
Ana Igea: The Barcelona Institute of Science and Technology
Pau Martin-Malpartida: The Barcelona Institute of Science and Technology
Lidia Ruiz: The Barcelona Institute of Science and Technology
Chiara Pallara: Nostrum Biodiscovery
Mauricio Esguerra: Nostrum Biodiscovery
Francesco Colizzi: The Barcelona Institute of Science and Technology
Cristina Mayor-Ruiz: The Barcelona Institute of Science and Technology
Ricardo M. Biondi: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)-CONICET-Partner Institute of the Max Planck Society
Robert Soliva: Nostrum Biodiscovery
Maria J. Macias: The Barcelona Institute of Science and Technology
Modesto Orozco: The Barcelona Institute of Science and Technology
Angel R. Nebreda: The Barcelona Institute of Science and Technology

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-39051-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39051-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-39051-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().