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Preclinical evaluation of the novel multi-targeted agent R1530
Kenneth Kolinsky1, Christian Tovar, Yu-E Zhang
1Discovery Oncology, Hoffmann-La Roche Inc, Nutley, NJ 07110, USA.
Purpose:
This study describes the antiproliferative activity of the multikinase inhibitor R1530 in vitro and its antitumor and anti-angiogenic activity, pharmacokinetics, and tolerability in vivo.
Methods:
The antiproliferative activity of R1530 was investigated in a range of human tumor, endothelial and fibroblast cell lines. Tolerability and antitumor activity were assessed in mice bearing a range of human tumor xenografts, and anti-angiogenic properties were established in the murine corneal pocket assay. R1530 pharmacokinetics in mice were established.
Results:
R1530 strongly inhibited human tumor cell proliferation. Growth factor-driven proliferation of endothelial and fibroblast cells was also inhibited. Significant tumor growth inhibition was demonstrated in a lung cancer xenograft model with a range of once daily, weekly and twice-weekly doses of R1530 (3.125-50 mg/kg qd, 100 mg/kg qw, 100 mg/kg biw). Daily doses were most effective in the lung cancer model and also had significant growth inhibitory effects in models of colorectal, prostate, and breast tumors. Tumor regression occurred in all models treated with the maximum tolerated daily dose (50 mg/kg). The doses of 25 and 50 mg/kg qd resulted in biologically significant increased survival in all tested models. After oral administration in nude mice, R1530 showed good tissue penetration. Exposure was dose dependent up to 100 mg/kg with oral administration.
Conclusions:
R1530 has demonstrated activity against a range of tumor models in vitro and in vivo and is an effective inhibitor of angiogenesis. These findings support the approach of targeting multiple pathways in the search for potential agents with improved anticancer properties.
Insights
The multikinase inhibitor R1530 shows strong antiproliferative and antitumor effects in vitro and in vivo. It also inhibits angiogenesis, demonstrating potential as an anticancer agent by targeting multiple pathways.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Multikinase inhibitors are crucial in cancer therapy.
- Targeting multiple signaling pathways offers a promising strategy for novel anticancer agents.
Purpose of the Study:
- To evaluate the in vitro antiproliferative activity of R1530.
- To assess the in vivo antitumor, anti-angiogenic, and pharmacokinetic properties of R1530.
Main Methods:
- In vitro antiproliferative assays using human tumor, endothelial, and fibroblast cell lines.
- In vivo studies in mice with human tumor xenografts for antitumor and tolerability assessment.
- Murine corneal pocket assay for anti-angiogenic properties and pharmacokinetic analysis.
Main Results:
- R1530 demonstrated potent inhibition of human tumor cell proliferation and angiogenesis.
- Significant tumor growth inhibition and regression were observed in various xenograft models, particularly with daily dosing.
- R1530 exhibited good tissue penetration and dose-dependent exposure after oral administration.
Conclusions:
- R1530 exhibits significant anticancer and anti-angiogenic activity across multiple tumor models.
- These findings support the development of R1530 as a potential therapeutic agent targeting multiple cancer pathways.
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