Brivanib (BMS-540215)|649735-46-6|安捷凯

Background

Brivanib is an ATP competitive inhibitor of human VEGFR-2 with IC50 value of 25nM [1].

Brivanib is a selective RTK inhibitor that targets signaling via VEGFR2 and 3, and FGFR1, 2 and 3. Targeting both VEGF and FGF signaling pathways inhibits tumor growth in RT2 mice, with VEGF signaling predominating in initiation of tumor angiogenesis, Currently, brivanib therapy is being evaluated in phase III clinical trials in colorectal carcinoma and hepatocellular carcinoma (HCC) and in phase II trials for numerous indications including brivanib second-line therapy following sorafenib failure [2].

Brivanib has moderate potency against VEGFR-1 and FGFR-1 and good selectivity against PDGFR-β. In the preclinical in vivo mouse models, it is also found to be a good inhibitor of Flk-1, the mouse homologue of VEGFR-2 with IC50 value of 89 nM. Brivanib is reported to inhibit the proliferation of human umbilical vein endothelial cells (HUVEC) with potency against VEGF-stimulated HUVECs and FGF-stimulated HUVECs. The IC50 values are 40 nM and 276nM respectively. When tested against human tumor cell lines, Brivanib shows lower antiproliferative potency. In particular, activity was low against the cell line used in the in vivo tumor xenograft mouse efficacy model (H3396) [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.

Protocol

Cell experiment:

Viability is measured in LX-2 cells using the Cell Counting Kit-8 (CCK-8). Using 96-well plates with 2,000 cells per well, HSCs are incubated in 10% FBS-supplemented DMEM for 24 hours, followed by starvation in serum-free media. After 24 hours of starvation, brivanib is added at different doses. Two hours later, 5 ng/mL PDGF-BB is added. The cells are incubated for an additional 72 hours and cell viability is measured. Each experiment is performed in three replicates at least four times.

Animal experiment:

Male mice 4-6 weeks of age are treated 3 times a week with a total of 12 intraperitoneal (i.p.) injections of 150 mL/kg TAA. At the onset of TAA treatment, placebo or brivanib (25 or 50 mg/kg) is administered orally on 5 consecutive days with weekend breaks. The animals are sacrificed 4 weeks after the start of the injections.

参考文献:

[1]. Bhide RS, et al. 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. J Med Chem, 2006, 49 (7), 2143-2146.
[2]. Huynh H, et al. Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin Cancer Res, 2008,
[3]. Nakamura I, et al. Correction: Brivanib Attenuates Hepatic Fibrosis In Vivo and Stellate Cell Activation In Vitro by Inhibition of FGF, VEGF and PDGF Signaling. PLoS One. 2015 Nov 3;10(11):e0142355.

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Brivanib (BMS-540215)

Brivanib (BMS-540215)详情

Background

Protocol

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