isoforms offers the prospect of enhanced efficacy as well as reduced potential for resistance. Described herein is the discovery and characterization of a series of pyrimidine scaffold with DFG-out conformation as potent Pan-Raf inhibitors. Among them, I-41 with excellent Pan-Raf potency demonstrates inhibitory activity against BRafWT phenotypic melanoma and BRafV600E phenotypic colon cells. The western
同时靶向所有Raf同工型提供了增强的功效以及降低的抗药性的前景。本文描述了一系列具有强力泛肽
抑制剂的具有DFG-out构象的
嘧啶支架的发现和表征。其中,具有优异泛泛效能的I-41表现出对BRafWT表型黑素瘤和BRafV600E表型结肠细胞的抑制活性。Western blotting结果显示,人黑素瘤SK-Mel-2
细胞系中Erk的抑制作用表明I-41抑制了SK-Mel-2细胞的增殖而没有Erk的反常激活,这支持I-41可能成为良好的候选化合物。克服黑素瘤对当前BRafV600E
抑制剂疗法的耐药性。I-41在大鼠中也具有良好的药代动力学特征。合成,
SAR,线索选择,