Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, 130-650, Korea.
Arch Pharm Res. 2012 Mar;35(4):605-15. doi: 10.1007/s12272-012-0403-5. Epub 2012 May 3.
Aberrant activation of Raf signaling pathway is frequently found in various human tumors, it has been considered as distinct and promising molecular target for cancer therapeutics. B-Raf is most attractive drug target out of three Raf isoforms (A-Raf, B-Raf and C-Raf) because it exhibits high kinase activity due to frequent mutations in human tumors. However, most recently, it has been reported that Raf isoforms show the cross-activation in the presence of specific B-Raf inhibitors, which brings about the paradoxical p-ERK activation as well as tumor promoting effect. According to these findings, it remains controversy whether pan-Raf kinase inhibitor is more valuable and promising rather than specific B-Raf inhibitor under certain conditions in terms of cancer therapeutics. In this short review, novel Raf kinase inhibitors undergoing clinical investigation are introduced. Moreover, the paradoxical p-ERK activation is discussed with specific B-Raf inhibitors, PLX4032/4720 compounds.
Raf 信号通路的异常激活在各种人类肿瘤中经常被发现，它已被认为是癌症治疗的独特而有前途的分子靶点。B-Raf 是三个 Raf 同工型（A-Raf、B-Raf 和 C-Raf）中最具吸引力的药物靶点，因为它在人类肿瘤中经常发生突变，表现出高激酶活性。然而，最近有报道称，在特定的 B-Raf 抑制剂存在下，Raf 同工型显示出交叉激活，导致矛盾的 p-ERK 激活以及肿瘤促进作用。根据这些发现，在癌症治疗方面，在某些情况下，pan-Raf 激酶抑制剂是否比特定的 B-Raf 抑制剂更有价值和更有前途仍然存在争议。在这篇简短的综述中，介绍了正在进行临床研究的新型 Raf 激酶抑制剂。此外，还讨论了与特定的 B-Raf 抑制剂 PLX4032/4720 化合物相关的矛盾的 p-ERK 激活。
