Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382 481, Gujarat, India.
Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382 481, Gujarat, India.
Eur J Med Chem. 2018 Jan 1;143:1103-1138. doi: 10.1016/j.ejmech.2017.08.044. Epub 2017 Aug 24.
c-Met is a prototype member of a subfamily of heterodimeric receptor tyrosine kinases (RTKs) and is the receptor for hepatocyte growth factor (HGF). Binding of HGF to its receptor c-Met, initiates a wide range of cellular signalling, including those involved in proliferation, motility, migration and invasion. Importantly, dysregulated HGF/c-Met signalling is a driving factor for numerous malignancies and promotes tumour growth, invasion, dissemination and/or angiogenesis. Dysregulated HGF/c-Met signalling has also been associated with poor clinical outcomes and resistance acquisition to some approved targeted therapies. Thus, c-Met kinase has emerged as a promising target for cancer drug development. Different therapeutic approaches targeting the HGF/c-Met signalling pathway are under development for targeted cancer therapy, among which small molecule inhibitors of c-Met kinase constitute the largest effort within the pharmaceutical industry. The review is an effort to summarize recent advancements in medicinal chemistry development of small molecule c-Met kinase inhibitors as potential anti-cancer agents which would certainly help future researchers to bring further developments in the discovery of small molecule c-Met kinase inhibitors.
c-Met 是受体酪氨酸激酶 (RTKs) 亚家族的原型成员,也是肝细胞生长因子 (HGF) 的受体。HGF 与其受体 c-Met 结合,启动广泛的细胞信号转导,包括参与增殖、运动、迁移和侵袭的信号转导。重要的是,失调的 HGF/c-Met 信号转导是许多恶性肿瘤的驱动因素,并促进肿瘤生长、侵袭、扩散和/或血管生成。失调的 HGF/c-Met 信号转导也与不良的临床结果和对一些已批准的靶向治疗药物的耐药性获得有关。因此,c-Met 激酶已成为癌症药物开发的有前途的靶点。针对 HGF/c-Met 信号通路的不同治疗方法正在开发中,用于靶向癌症治疗,其中 c-Met 激酶小分子抑制剂是制药行业最大的努力。该综述旨在总结小分子 c-Met 激酶抑制剂作为潜在抗癌药物的药物化学发展的最新进展,这肯定有助于未来的研究人员在小分子 c-Met 激酶抑制剂的发现方面取得进一步的发展。