Daiichi Sankyo India Pharma Private Limited, Gurgaon, India; Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India.
Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India.
Pharmacol Rep. 2017 Aug;69(4):746-756. doi: 10.1016/j.pharep.2017.03.023. Epub 2017 Apr 8.
The p38/MK2 pathway regulates a wide range of biological functions, and thus has most been explored as a therapeutic target for inhibition of severe and chronic inflammatory diseases. Till date, several p38 inhibitors with potent anti-inflammatory effects in pre-clinical models have been discovered, but most of them have failed in clinics due to serious systemic toxicity issues. MK2 is a serine-threonine kinase downstream to p38 and is activated directly through phosphorylation of p38 under stress and inflammatory stimulus. MK2 has been shown to be a direct and essential component in regulating the biosynthesis of pro-inflammatory cytokines. Disruption of MK2 signaling leads to a significant reduction in the level of several pro-inflammatory cytokine production. For these reasons, MK2 has been identified as an alternate molecular target in order to block the pathway with an assumption that this approach would show similar efficacy as that of p38 inhibitors with lesser toxicity concerns. This review briefly summarizes the molecular structure of MK2 and major biological functions in context with its pharmacological modulation to address various inflammatory diseases. It also discusses the points of advantages over p38 inhibition along with recent update in the development of small molecule MK2 inhibitors.
p38/MK2 通路调节广泛的生物学功能，因此最常被探索作为抑制严重和慢性炎症性疾病的治疗靶点。迄今为止，已经发现了几种在临床前模型中具有强大抗炎作用的 p38 抑制剂，但由于严重的全身毒性问题，大多数在临床上都失败了。MK2 是 p38 的丝氨酸-苏氨酸激酶，在应激和炎症刺激下通过 p38 的磷酸化而直接激活。MK2 已被证明是调节促炎细胞因子生物合成的直接和必需组成部分。阻断 MK2 信号会导致几种促炎细胞因子产生水平显著降低。基于这些原因，MK2 已被确定为替代分子靶标，以阻断该通路，假设这种方法与 p38 抑制剂具有相似的疗效，而毒性问题较少。本综述简要总结了 MK2 的分子结构及其在药理学调节方面的主要生物学功能，以解决各种炎症性疾病。它还讨论了与 p38 抑制相比的优势，并介绍了小分子 MK2 抑制剂的最新进展。
