Gaestel M, Mengel A, Bothe U, Asadullah K
Department of Biochemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Curr Med Chem. 2007;14(21):2214-34. doi: 10.2174/092986707781696636.
The human kinome describes a major group of intracellular signalling molecules. In the last few years, many molecules in the group have become targets for therapeutic interventions. Due to the conserved reaction mechanism of catalysis, protein kinases seem well "drugable" by small molecular weight inhibitors, thus opening the chance to novel oral bioavailable drug development. A large number of small molecule weight inhibitors for protein kinases have already been introduced into research and these molecules are extensively analysed in regard to their efficiency, potency and selectivity. Here we summarise the use of small molecule protein kinase inhibitors relevant for acute and chronic inflammation based on their essential role in cellular signaling mechanisms in immune cells such as macrophages, lymphoytes and granulocytes. We describe the progress made to develop inhibitors against Toll-like receptor associated kinases (IRAKs), against the MAPK kinase kinases Cot/Tpl-2 and TAK1, against Inhibitor-kappaB kinases (IKKs), against MAPK kinases (MEKs, MKKs), against MAPKs (ERK2, p38, JNKs) and against their downstream kinases MNK1 and MK2/3. This overview should help to keep up with the fast developing field and the continuously growing number of protein kinase inhibitors.
人类激酶组描述了一大类细胞内信号分子。在过去几年中，该组中的许多分子已成为治疗干预的靶点。由于催化反应机制保守，蛋白激酶似乎很容易被小分子抑制剂“靶向”，从而为新型口服生物可利用药物的开发提供了机会。大量用于蛋白激酶的小分子抑制剂已被引入研究，并且对这些分子的效率、效力和选择性进行了广泛分析。在此，我们基于小分子蛋白激酶抑制剂在巨噬细胞、淋巴细胞和粒细胞等免疫细胞的细胞信号传导机制中的重要作用，总结其在急性和慢性炎症中的应用。我们描述了在开发针对Toll样受体相关激酶（IRAKs）、丝裂原活化蛋白激酶激酶激酶Cot/Tpl-2和TAK1、IκB激酶（IKKs）、丝裂原活化蛋白激酶激酶（MEKs、MKKs）、丝裂原活化蛋白激酶（ERK2、p38、JNKs）及其下游激酶MNK1和MK2/3的抑制剂方面所取得的进展。本综述应有助于跟上这一快速发展的领域以及蛋白激酶抑制剂数量不断增加的步伐。
