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

16 pages, 10 figures, supplementary information https://doi.org/10.1038/s41467-023-39051-x.-- Data availability: The diffraction data and coordinates of the p38α complexes bound to NC-p38i compounds have been deposited in the Protein Data Bank under accession codes 7PVU, 7Z6I and 7Z9T. We have also used the following PDB structures: 4LOO, 1A9U, 3COI, 7N8T, 2ZOQ, 1PME, 3GC9, 1CM8, 4UX9. Source data are provided with this paper
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
This work was supported by grants from the Spanish Ministerio de Ciencia e Innovación (MICINN, PID2019-109521RB-I00 and PID2021-122478NB-I00), the BioMedTec program of IRB-Fundació La Caixa, the European Research Council (Proof of Concept p38_InTh-825763), AGAUR (2016 LLAV 00043 and 2019 PROD 00138 supported by FEDER, and 2017 SGR-557, 2017 SGR-50, 2021 SGR-909, and 2021 SGR-866), BBVA Foundation, and the European Union’s Horizon 2020 research and innovation program (euCanSHare 825903 and BioExcel-3 101093290). L.G. and B.B. were funded by predoctoral contracts from MICINN (BES-2016-077122) and the Marie Skłodowska-Curie COFUND action of IRB Barcelona and the PREBIST Predoc Programme (PREBIST_754558), respectively. F.C. is a Ramon y Cajal Fellow (RYC2019-026768-I). Access to ALBA was granted through the BAG proposals 2018092972 and 2020094472. We gratefully acknowledge institutional funding from IRB Barcelona, the CERCA Programme of the Catalan Government, and the MICINN through the Centres of Excellence Severo Ochoa award. M.J.M. and A.R.N. are supported by the Institució Catalana de Recerca i Estudis Avancats (ICREA)
With the institutional support of the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S)