AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
J Med Chem. 2015 Jan 8;58(1):278-93. doi: 10.1021/jm501038s. Epub 2014 Oct 9.
Two structurally distinct series of novel, MAPK-activated kinase-2 prevention of activation inhibitors have been discovered by high throughput screening. Preliminary structure-activity relationship (SAR) studies revealed substructural features that influence the selective inhibition of the activation by p38α of the downstream kinase MK2 in preference to an alternative substrate, MSK1. Enzyme kinetics, surface plasmon resonance (SPR), 2D protein NMR, and X-ray crystallography were used to determine the binding mode and the molecular mechanism of action. The compounds bind competitively to the ATP binding site of p38α but unexpectedly with higher affinity in the p38α-MK2 complex compared with p38α alone. This observation is hypothesized to be the origin of the substrate selectivity. The two lead series identified are suitable for further investigation for their potential to treat chronic inflammatory diseases with improved tolerability over previously studied p38α inhibitors.
通过高通量筛选，发现了两种结构截然不同的新型 MAPK 激活激酶-2 激活抑制剂。初步的结构-活性关系（SAR）研究揭示了影响选择性抑制 p38α 对下游激酶 MK2 的激活而不是对替代底物 MSK1 的激活的亚结构特征。酶动力学、表面等离子体共振（SPR）、二维蛋白质 NMR 和 X 射线晶体学用于确定结合模式和作用机制。这些化合物竞争性地结合到 p38α 的 ATP 结合位点，但出人意料的是，与单独的 p38α 相比，它们在 p38α-MK2 复合物中的结合亲和力更高。这一观察结果被假设为底物选择性的起源。所确定的两个主要系列适合进一步研究，以评估它们在治疗慢性炎症性疾病方面的潜力，与以前研究的 p38α 抑制剂相比，具有更好的耐受性。
