Brivanib (BMS-540215) is an orally active ATP-competitive inhibitor of VEGFR-2, with an IC50 of 25nM and Ki of 26nM [1]. Brivanib can inhibit the phosphorylation of FGFR1 and VEGFR2, and suppress the formation of choroidal neovascularization (CNV)[2]. Brivanib has been widely used to inhibit tumor progression in animal models and to prevent tumor angiogenesis[3].
In vitro, Brivanib treatment for 24 hours significantly inhibited the proliferation of Huh-7 cells, with an IC50 value of 8.6μM[4]. Treatment with 10μM Brivanib for 96 hours significantly inhibited dengue virus (DENV) infection of BHK-21 cells, reversed the decrease in AMPK phosphorylation levels caused by DENV infection, and improved the cellular lipid environment[5].
In vivo, Brivanib treatment via oral administration at a dose of 25mg/kg/day for 7 days significantly inhibited liver fibrosis induced by bile duct ligation (BDL) in mice and reduced the expression of collagen Iα1 mRNA[6]. Oral administration of 90mg/kg of Brivanib daily for 9 days significantly inhibited tumor growth in the L2987 xenograft mouse model[7].
References:
[1] Bhide R S, Cai Z W, Zhang Y Z, et al. Discovery and preclinical studies of (R)-1-(4-(4-Fluoro-2-methyl-1 H-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[J]. Journal of medicinal chemistry, 2006, 49(7): 2143-2146.
[2] Li L, Zhu M, Wu W, et al. Brivanib, a multitargeted small‐molecule tyrosine kinase inhibitor, suppresses laser‐induced CNV in a mouse model of neovascular AMD[J]. Journal of Cellular Physiology, 2020, 235(2): 1259-1273.
[3] Allen E, Walters I B, Hanahan D. 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[J]. Clinical Cancer Research, 2011, 17(16): 5299-5310.
[4] Kim H, Lim H Y. Novel EGFR-TK inhibitor EKB-569 inhibits hepatocellular carcinoma cell proliferation by AKT and MAPK pathways[J]. Journal of Korean Medical Science, 2011, 26(12): 1563.
[5] Wan Y, Wu W, Wan Y, et al. Brivanib alaninate inhibited dengue virus proliferation through VEGFR2/AMPK pathway[J]. Pharmacological Research, 2021, 170: 105721.
[6] Nakamura I, Zakharia K, Banini B A, et al. Brivanib attenuates hepatic fibrosis in vivo and stellate cell activation in vitro by inhibition of FGF, VEGF and PDGF signaling[J]. PloS one, 2014, 9(4): e92273.
[7] Marathe P H, Kamath A V, Zhang Y, et al. Preclinical pharmacokinetics and in vitro metabolism of brivanib (BMS-540215), a potent VEGFR2 inhibitor and its alanine ester prodrug brivanib alaninate[J]. Cancer chemotherapy and pharmacology, 2009, 65(1): 55-66.
Brivanib (BMS-540215)是一种口服有效的ATP竞争性VEGFR-2抑制剂，IC50为25nM，Ki为26nM[1]。Brivanib可抑制FGFR1和VEGFR2的磷酸化，并抑制脉络膜新生血管(CNV)的形成[2]。Brivanib已被广泛用于抑制动物模型中的肿瘤进展和预防肿瘤血管生成[3]。
在体外，Brivanib处理24小时显著抑制了Huh-7细胞的增殖，IC50值为8.6μM[4]。使用10μM的Brivanib处理BHK-21细胞96小时，显著抑制了登革热病毒(DENV)对细胞的感染，逆转了DENV感染引起的AMPK磷酸化水平下降，并改善了细胞脂质环境[6]。
在体内，每日口服25mg/kg剂量的Brivanib，连续7天，显著抑制了胆管结扎(BDL)诱导的小鼠肝纤维化，并降低了胶原蛋白Iα1 mRNA的表达[6]。每日口服90mg/kg剂量的Brivanib，连续9天，显著抑制了L2987异种移植小鼠模型中的肿瘤生长[7]。