Asati Vivek, Bharti Sanjay K, Mahapatra Debarshi K
Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur- 495009, Chhattisgarh, India.
Anticancer Agents Med Chem. 2016;16(12):1558-1575. doi: 10.2174/1871520616666160606101848.
The Ras/Raf/MEK/ERK signaling pathway involves various kinases in which each kinase is associated with one another through signals and regulates cell proliferation, differentiation and apoptosis. This pathway is dysregulated almost in all cancers due to the amplification and genetic mutation of various components of the pathway. The genetic mutations have been reported to cause drug resistance to the current chemotherapy of melanomas. B-Raf is one of the most commonly mutated proto-oncogenes and plays a significant role in the development of numerous cancers of high clinical impact. Therefore, mutant B-Raf kinase may be a promising therapeutic target for the development of novel anticancer drugs. Many BRAF inhibitors discovered during the last decade showed promising anticancer activity, especially on tumors that harbor BRAFV600E mutations. Currently, vemurafenib and dabrafenib are USFDA approved drugs used as B-Raf inhibitors. Few drugs which are under clinical development phases such as LGX818, GDC0879, XL281, ARQ736, PLX3603 (RO5212054), and RAF265 etc. pave the path for further designing of B-Raf inhibitors. The present review focuses primarily on the Ras/Raf/MEK/ERK signaling pathway with mutant B-Raf as a therapeutic target for anticancer drug development. The essential pharmacophoric features of B-Raf inhibitors, their structure activity relationships (SARs) and molecules under clinical trials have been highlighted.
Ras/Raf/MEK/ERK信号通路涉及多种激酶，其中每种激酶通过信号相互关联，并调节细胞增殖、分化和凋亡。由于该通路各种组分的扩增和基因突变，几乎在所有癌症中该通路都会失调。据报道，基因突变会导致黑色素瘤对当前化疗产生耐药性。B-Raf是最常发生突变的原癌基因之一，在众多具有高临床影响的癌症发展中起重要作用。因此，突变型B-Raf激酶可能是开发新型抗癌药物的一个有前景的治疗靶点。在过去十年中发现的许多BRAF抑制剂显示出有前景的抗癌活性，尤其是对携带BRAFV600E突变的肿瘤。目前，维莫非尼和达拉非尼是美国食品药品监督管理局批准用作B-Raf抑制剂的药物。少数处于临床开发阶段的药物，如LGX818、GDC0879、XL281、ARQ736、PLX3603（RO5212054）和RAF265等，为进一步设计B-Raf抑制剂铺平了道路。本综述主要关注以突变型B-Raf作为抗癌药物开发治疗靶点的Ras/Raf/MEK/ERK信号通路。重点介绍了B-Raf抑制剂的基本药效特征、它们的构效关系（SARs）以及正在进行临床试验的分子。
