Department of Immunology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
Bioorg Med Chem Lett. 2013 Jul 15;23(14):4120-6. doi: 10.1016/j.bmcl.2013.05.047. Epub 2013 May 23.
A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38β isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed.
已鉴定出一系列新型 p38 MAP 激酶抑制剂，它们对 p38α 同工型具有高度选择性，相对于其他家族成员（包括高度同源的 p38β 同工型）具有高度选择性。X 射线共晶结构研究揭示了代表类似物 5c 和 9d 在 p38α 中的前所未有的激酶结合模式，其中 p38α 铰链区域内发生 Leu108/Met109 肽翻转。基于这些发现，提出了通过针对这种新型结合模式来合理设计其他有前途的 p38α 同工型选择性抑制剂的一般策略。
