Ganguly Payal, Macleod Tom, Wong Chi, Harland Mark, McGonagle Dennis
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds LS9 7JT, UK.
Pharmaceuticals (Basel). 2023 Sep 12;16(9):1286. doi: 10.3390/ph16091286.
The p38 mitogen-activated protein kinase (p38-MAPK) is a crucial signaling pathway closely involved in several physiological and cellular functions, including cell cycle, apoptosis, gene expression, and responses to stress stimuli. It also plays a central role in inflammation and immunity. Owing to disparate p38-MAPK functions, it has thus far formed an elusive drug target with failed clinical trials in inflammatory diseases due to challenges including hepatotoxicity, cardiac toxicity, lack of efficacy, and tachyphylaxis, which is a brief initial improvement with rapid disease rebound. To overcome these limitations, downstream antagonism of the p38 pathway with a MAPK-activated protein kinase (MAPKAPK, also known as MK2) blockade has demonstrated the potential to abrogate inflammation without the prior recognized toxicities. Such MK2 inhibition (MK2i) is associated with robust suppression of key pro-inflammatory cytokines, including TNFα and IL-6 and others in experimental systems and in vitro. Considering this recent evidence regarding MK2i in inflammatory arthritis, we revisit the p38-MAPK pathway and discuss the literature encompassing the challenges of p38 inhibitors with a focus on this pathway. We then highlight how novel MK2i strategies, although encouraging in the pre-clinical arena, may either show evidence for efficacy or the lack of efficacy in emergent human trials data from different disease settings.
p38丝裂原活化蛋白激酶（p38-MAPK）是一条关键的信号通路，紧密参与多种生理和细胞功能，包括细胞周期、细胞凋亡、基因表达以及对应激刺激的反应。它在炎症和免疫中也起着核心作用。由于p38-MAPK功能多样，它至今已成为一个难以捉摸的药物靶点，在炎症性疾病的临床试验中失败，原因包括肝毒性、心脏毒性、缺乏疗效以及快速耐受，快速耐受是指最初有短暂改善但疾病迅速反弹。为克服这些局限性，通过阻断丝裂原活化蛋白激酶激活的蛋白激酶（MAPKAPK，也称为MK2）对p38通路进行下游拮抗，已显示出在无先前公认毒性的情况下消除炎症的潜力。这种MK2抑制（MK2i）在实验系统和体外与强力抑制关键促炎细胞因子有关，包括肿瘤坏死因子α（TNFα）、白细胞介素-6（IL-6）等。考虑到最近关于MK2i在炎症性关节炎方面的证据，我们重新审视p38-MAPK通路，并讨论围绕p38抑制剂挑战的文献，重点关注该通路。然后我们强调，尽管新型MK2i策略在临床前领域令人鼓舞，但在来自不同疾病背景的新兴人体试验数据中，可能显示出疗效证据，也可能显示出无效证据。
