Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028, Barcelona, Spain.
Nostrum Biodiscovery, 08034, Barcelona, Spain.
Nat Commun. 2023 Jun 12;14(1):3318. doi: 10.1038/s41467-023-39051-x.
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.
p38α 是一种多功能蛋白激酶，能够控制众多过程，并在细胞对应激的反应中发挥重要作用。p38α 信号的失调与包括炎症、免疫紊乱和癌症在内的多种疾病有关，这表明靶向 p38α 可能具有治疗益处。在过去的二十年中，已经开发出了许多 p38α 抑制剂，它们在临床前研究中显示出了有前景的效果，但临床试验的结果却令人失望，这激发了人们对开发 p38α 调节替代机制的兴趣。在这里，我们报告了化合物的计算鉴定，我们称之为非典型 p38α 抑制剂（NC-p38i）。通过结合生化和结构分析，我们表明 NC-p38i 能够有效地抑制 p38α 自身磷酸化，但对典型途径的活性影响较弱。我们的结果展示了如何利用 p38α 的结构可塑性来开发针对该途径调节的一部分功能的治疗机会。
