Brivanib (BMS-540215)

Brivanib是一种ATP竞争性的人VEGFR-2抑制剂，IC50值为25 nM[1]。

Brivanib是一种选择性RTK抑制剂，以通过VEGFR2和3及FGFR1、2和3的信号为靶标。在RT2小鼠中，Brivanib可靶向VEGF和FGF信号通路，抑制肿瘤生长，而VEGF信号在肿瘤血管生成的起始中起主导作用，目前，brivanib治疗正用于结肠癌和肝癌（HCC）的III期临床试验评估，在II期临床试验中也已众多迹象，包括sorafenib治疗无效的brivanib二线治疗[2]。

Brivanib对VEGFR-1和FGFR-1有适度的效力，与PDGFR-β相比有较好的选择性。临床前小鼠模型的体内实验也发现Brivanib是小鼠VEGFR-2同源物Flk-1的良好抑制剂，IC50值为89 nM。Brivanib可抑制人脐静脉内皮细胞（HUVEC）增殖，对VEGF诱发的HUVEC和FGF诱发的HUVEC具有抑制能力，IC50值分别为40 nM和276 nM。在人肿瘤细胞系中，Brivanib显示出较低的抗增殖效力。特别地，对体内肿瘤异种移植小鼠功效模型（H3396）中使用的细胞系活性低[1]。

参考文献：
[1] Rajeev S.  Bhide, Zhen-Wei Cai, Yong-Zheng Zhang, Ligang Qian, Donna Wei, Stephanie Barbosa, Louis J. Lombardo, Robert M. Borzilleri, Xiaoping Zheng, Laurence I. Wu, Joel C. Barrish, Soong-Hoon Kim, Kenneth Leavitt, Arvind Mathur, Leslie Leith, Sam Chao, Barri Wautlet, Steven Mortillo, Robert Jeyaseelan Sr., Daniel Kukral, John T. Hunt, Amrita Kamath, Aberra Fura, Viral Vyas, Punit Marathe, Celia D’Arienzo, George Derbin, and Joseph Fargnoli. Discovery and Preclinical Studies of (R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (BMS-540215), an In Vivo Active Potent VEGFR-2 Inhibitor. Journal of Medicinal Chemistry. 2006, 49 (7): 2143-2146.
[2] Elizabeth Allen, Ian B.  Walters, and Douglas Hanahan. Brivanib, a Dual FGF/VEGF Inhibitor, Is Active Both First and Second Line against Mouse Pancreatic Neuroendocrine Tumors Developing Adaptive/Evasive Resistance to VEGF Inhibition. Clinical Cancer Research. 2011 (17): 5299-5310.