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

Bhide, Rajeev S.; Cai, Zhen-Wei; Zhang, Yongzheng; Qian, Ligang; Wei, Donna; Barbosa, Stephanie A. Lodise; Lombardo, Louis J.; Borzilleri, R. M.; Zheng, Xiaoping; Wu, Laurence I.; Barrish, Joel C.; Kim, Soong‐Hoon; Leavitt, Kenneth J.; Mathur, Arvind; Leith, Leslie; Chao, Sam; Wautlet, Barri; Mortillo, Steven; Jeyaseelan, Robert; Kukral, Daniel; Hunt, John T.; Kamath, Amrita V.; Fura, Aberra; Vyas, Viral; Marathe, Punit; D’Arienzo, Celia; Derbin, George; Fargnoli, Joseph

doi:10.1021/jm051106d

Cited by 128 publications

(54 citation statements)

References 13 publications

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“…The exact mechanisms by which brivanib treatment induces growth inhibition are not well understood. A previous study (13) has shown that brivanib affected the host endothelium based on both in vitro and in vivo studies (vascular density, Matrigel plugs, and dynamic contrast-enhanced magnetic resonance imaging responses). It had no antiproliferative effects on L2987 lung carcinoma, HCT116 colon carcinoma, H3396 breast carcinoma, and CWR-22 prostate carcinoma cell lines in culture.…”

Section: Discussionmentioning

confidence: 99%

“…BMS-540215 shows potent and selective inhibition of VEGFR and fibroblast growth factor receptor (FGFR) tyrosine kinases (13). The structures of brivanib and BMS-540215 are shown in Fig.…”

mentioning

confidence: 99%

“…BMS-540215 also showed good selectivity for FGFR-1 (IC 50 = 148 nmol/L), FGFR-2 (IC 50 = 125 nmol/L), and FGFR-3 (IC 50 = 68 nmol/L). Furthermore, BMS-540215 has been shown to selectively inhibit the proliferation of endothelial cells stimulated by VEGF and FGF in vitro with IC 50 values of 40 and 276 nmol/L, respectively (13). It also shows broad-spectrum in vivo antitumor activity over multiple dose levels and induces stasis in large tumors, suggesting that it may have a role in the treatment of HCC.…”

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confidence: 99%

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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

Huynh

Ngo

Fargnoli³

et al. 2008

Clinical Cancer Research

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206

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Purpose: Hepatocellular carcinoma (HCC) is the fifth most common primary neoplasm; surgery is the only curative option but 5-year survival rates are only 25% to 50%. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are known to be involved in growth and neovascularization of HCC. Therefore, agents that target these pathways may be effective in the treatment of HCC. The aim of this study was to determine the antineoplastic activity of brivanib alaninate, a dual inhibitor of VEGF receptor (VEGFR) and FGF receptor (FGFR) signaling pathways. Experimental Design: Six different s.c. patient-derived HCC xenografts were implanted into mice. Tumor growth was evaluated in mice treated with brivanib compared with control. The effects of brivanib on apoptosis and cell proliferation were evaluated by immunohistochemistry. The SK-HEP1 and HepG2 cells were used to investigate the effects of brivanib on the VEGFR-2 and FGFR-1 signaling pathways in vitro. Western blotting was used to determine changes in proteins in these xenografts and cell lines. Results: Brivanib significantly suppressed tumor growth in five of six xenograft lines. Furthermore, brivanib–induced growth inhibition was associated with a decrease in phosphorylated VEGFR-2 at Tyr1054/1059, increased apoptosis, reduced microvessel density, inhibition of cell proliferation, and down-regulation of cell cycle regulators. The levels of FGFR-1 and FGFR-2 expression in these xenograft lines were positively correlated with its sensitivity to brivanib-induced growth inhibition. In VEGF-stimulated and basic FGF stimulated SK-HEP1 cells, brivanib significantly inhibited VEGFR-2, FGFR-1, extracellular signal-regulated kinase 1/2, and Akt phosphorylation. Conclusion: This study provides a strong rationale for clinical investigation of brivanib in patients with HCC.

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Section: Discussionmentioning

confidence: 99%

“…BMS-540215 shows potent and selective inhibition of VEGFR and fibroblast growth factor receptor (FGFR) tyrosine kinases (13). The structures of brivanib and BMS-540215 are shown in Fig.…”

mentioning

confidence: 99%

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confidence: 99%

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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

Huynh

Ngo

Fargnoli³

et al. 2008

Clinical Cancer Research

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“…Brivanib alaninate, the orally administrated L-alanine ester prodrug, has strong antiangiogenic effects, as well as potent direct effects, on tumor cells across a range of tumor types, including liver and colon. [66][67][68][69] Sorafenib, 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide 4-methylbenzenesulfonate, a kinase inhibitor of VEGFR, PDGFR, c-Kit, and Raf, has been approved for the treatment of hepatocellular carcinoma. Because brivanib targets both the FGF and VEGF signaling pathways, it may gain an advantage over sorafenib for the treatment of hepatocellular carcinoma.…”

Section: Fgfr-targetedmentioning

confidence: 99%

Receptor Tyrosine Kinases and Targeted Cancer Therapeutics

Takeuchi

Ito

2011

Biological & Pharmaceutical Bulletin

144

113

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The majority of growth factor receptors are composed of extracellular, transmembrane, and cytoplasmic tyrosine kinase (TK) domains. Receptor tyrosine kinase (RTK) activation regulates many key processes including cell growth and survival. However, dysregulation of RTK has been found in a wide range of cancers, and it has been shown to correlate with the development and progression of numerous cancers. Therefore, RTK has become an attractive therapeutic target. One way to effectively block signaling from RTK is inhibition of its catalytic activity with small-molecule inhibitors. Low-molecular-weight TK inhibitors (TKIs), such as imatinib, targeting tumors with mutant c-Kit, and gefitinib, targeting non-small cell lung cancer with mutant epidermal growth factor receptor (EGFR), have received marketing approval in Japan. MET, fibroblast growth factor receptor (FGFR), and insulin-like growth factor-I receptor (IGF-IR) are frequently genetically altered in advanced cancers. TKIs of these receptors have not yet appeared on the market, but many anticancer drug candidates are currently undergoing clinical trials. Most of these TKIs were designed to compete with ATP at the ATP-binding site within the TK domain. This review will focus on small-molecule TKIs targeting MET, FGFR, and IGF-IR and discuss the merits and demerits of two types of agents, i.e., those with only one or a few targets and those directed at multiple targets. Targeting agents specifically inhibiting the target kinase were previously searched for based on the hypothesis that a narrow target window might reduce unexpected side effects, but agents with multiple targets have been recently developed to overcome tumors resistant against a single-targeting agent.

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“…Due to the low aqueous solubility of brivanib, a prodrug strategy was pursued that resulted in a prodrug with high aqueous solubility, brivanib alaninate (13). Brivanib, the parent compound, has previously been shown to be a selective inhibitor of FGFR-1 and FGFR-2, and VEGFR-1, VEGFR-2, and VEGFR-3 in vitro (14,15). Additionally, brivanib has also shown antitumor activity in vivo against the H3396 human breast tumor xenograft model (14).…”

Section: Introductionmentioning

confidence: 99%

The Antiangiogenic Activity in Xenograft Models of Brivanib, a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor-2 and Fibroblast Growth Factor Receptor-1 Kinases

Bhide

Lombardo

Hunt

et al. 2010

Molecular Cancer Therapeutics

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Tumor angiogenesis is a complex and tightly regulated network mediated by various proangiogenic factors. The fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) family of growth factors, and associated tyrosine kinase receptors have a major influence in tumor growth and dissemination and may work synergistically to promote angiogenesis. Brivanib alaninate is the orally active prodrug of brivanib, a selective dual inhibitor of FGF and VEGF signaling. Here, we show that brivanib demonstrates antitumor activity in a broad range of xenograft models over multiple dose levels and that brivanib alaninate shows dose-dependent efficacy equivalent to brivanib in L2987 human tumor xenografts. Brivanib alaninate (107 mg/kg) reduced tumor cell proliferation as determined by a 76% reduction in Ki-67 staining and reduced tumor vascular density as determined by a 76% reduction in anti-CD34 endothelial cell staining. Furthermore, Matrigel plug assays in athymic mice showed that brivanib alaninate inhibited angiogenesis driven by VEGF or basic FGF alone, or combined. Dynamic contrast-enhanced magnetic resonance imaging, used to assess the effects of brivanib alaninate on tumor microcirculation, showed a marked decrease in gadopentetate dimeglumine contrast agent uptake at 107 mg/kg dose, with a reduction in area under the plasma concentrationtime curve from time 0 to 60 minutes at 24 and 48 hours of 54% and 64%, respectively. These results show that brivanib alaninate is an effective antitumor agent in preclinical models across a range of doses, and that efficacy is accompanied by changes in cellular and vascular activities. Mol Cancer Ther; 9(2); 369-78. ©2010 AACR.

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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

Cited by 128 publications

References 13 publications

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

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

Receptor Tyrosine Kinases and Targeted Cancer Therapeutics

The Antiangiogenic Activity in Xenograft Models of Brivanib, a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor-2 and Fibroblast Growth Factor Receptor-1 Kinases

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