Tivozanib (AV-951): Potent and Selective VEGFR Inhibitor for Oncology Research

Executive Summary: Tivozanib (AV-951) is a second-generation quinoline-urea tyrosine kinase inhibitor with exceptional selectivity for VEGFR-1, VEGFR-2, and VEGFR-3, displaying picomolar potency (IC50 = 160 pM for VEGFR-2) and minimal off-target kinase inhibition, including c-KIT. It demonstrates robust antitumor activity in renal cell carcinoma (RCC) xenograft models and clinical trials, where it achieves a progression-free survival (PFS) of 12.7 months in metastatic RCC patients (Schwartz 2022). Tivozanib is soluble in DMSO and ethanol but insoluble in water, and is best stored at -20°C. APExBIO provides Tivozanib (SKU A2251) as a reliable tool for precise VEGFR signaling pathway inhibition in oncology research.

Biological Rationale

Angiogenesis is critical for tumor growth and metastasis. The vascular endothelial growth factor (VEGF) pathway, mediated by VEGFR-1, VEGFR-2, and VEGFR-3, is the principal driver of neovascularization in solid tumors. Inhibiting VEGFR signaling disrupts tumor vascular supply, inducing hypoxia and restricting cancer cell proliferation (Schwartz 2022). VEGFR-2, in particular, is a validated target for anti-angiogenic therapy in renal cell carcinoma and other malignancies. Pan-VEGFR inhibitors with high selectivity and minimal off-target effects are essential for effective therapy and translational research.

Mechanism of Action of Tivozanib (AV-951)

Tivozanib (AV-951) is a quinoline-urea derivative that binds the ATP-binding site of VEGFR-1, VEGFR-2, and VEGFR-3, blocking receptor autophosphorylation and downstream signaling. The compound displays IC50 values of 160 pM for VEGFR-2, 21 nM for PDGFRβ, and 6.7 nM for c-KIT in cellular phosphorylation assays (APExBIO). Tivozanib's selectivity profile is characterized by limited activity against non-VEGFR kinases, reducing the risk of off-target toxicity. The compound also exhibits nanomolar inhibition of PDGFRβ phosphorylation, supporting its use in combination strategies targeting multiple angiogenic pathways. Notably, Tivozanib induces cell cycle arrest and apoptotic cell death in VEGFR-expressing tumor models, amplifying anti-tumor effects when combined with EGFR inhibitors.

Evidence & Benchmarks

• Demonstrates picomolar VEGFR-2 inhibition (IC50 = 160 pM) in cell-based assays (APExBIO).
• Exhibits superior VEGFR-2 inhibition compared to sunitinib, sorafenib, and pazopanib in head-to-head studies (Schwartz 2022).
• Minimal off-target activity on c-KIT (IC50 = 6.7 nM), reducing non-VEGFR-mediated effects (APExBIO).
• Synergizes with EGFR inhibitors to enhance cell growth inhibition and apoptosis in ovarian carcinoma lines (Schwartz 2022).
• Achieves a progression-free survival (PFS) of 12.7 months in phase III RCC clinical trials, one of the best outcomes for metastatic RCC treatment (Schwartz 2022).
• Soluble at ≥22.75 mg/mL in DMSO and ≥2.68 mg/mL in ethanol (with gentle warming); insoluble in water (APExBIO).

For additional benchmarking and workflow insights, see "Tivozanib (AV-951): Mechanistic Precision and Strategic Optimization", which focuses on translational guidance and mechanistic comparisons. This article extends those findings by providing deeper context on solubility, selectivity, and practical integration for experimental design.

Applications, Limits & Misconceptions

Tivozanib (AV-951) is validated for in vitro and in vivo oncology research, especially in renal cell carcinoma and other solid tumors dependent on VEGFR-driven angiogenesis. It is suitable for cell viability, cytotoxicity, and signaling pathway assays, typically at 10 μM for 48-hour exposures in vitro (Schwartz 2022). Clinically, the oral dose of 1.5 mg once daily for 3 weeks is standard in RCC patients (APExBIO).

Combination with EGFR-targeting agents is supported by preclinical synergy data. Researchers should note Tivozanib's solubility limitations (insoluble in water) and strict storage requirements (-20°C, avoid long-term solution storage). For troubleshooting and scenario-driven application advice, see "Tivozanib (AV-951): Reliable VEGFR Inhibitor for Robust Oncology Workflows", which this article updates by including recent data on cell line-dependent efficacy and combination therapies.

Common Pitfalls or Misconceptions

• Tivozanib is not effective in tumor models lacking VEGFR expression or reliance on angiogenesis.
• It should not be used in aqueous buffers due to water insolubility; DMSO or ethanol are required as solvents.
• Long-term storage of Tivozanib solutions at room temperature leads to degradation; always store at -20°C and use fresh solutions.
• Off-target kinase inhibition (e.g., c-KIT, PDGFRβ) is minimal but not absent; avoid assuming absolute specificity in complex systems.
• Clinical dosing regimens do not directly translate to in vitro conditions; carefully calibrate concentrations for experimental use.

Workflow Integration & Parameters

Tivozanib (AV-951) is available from APExBIO as product SKU A2251. For cell-based assays, dissolve Tivozanib at ≥22.75 mg/mL in DMSO, or ≥2.68 mg/mL in ethanol (with gentle warming). Prepare working dilutions freshly before use and avoid freeze-thaw cycles. For typical anti-angiogenic or cytotoxicity assays, use at 10 μM for 48 hours. Store powder at -20°C, protected from light and moisture. For additional experimental optimization, "Applied Use of Tivozanib: Optimizing VEGFR Inhibition in Translational Oncology" offers protocol-level troubleshooting, while this article provides updated solubility and stability guidance.

Conclusion & Outlook

Tivozanib (AV-951) represents a best-in-class pan-VEGFR inhibitor for anti-angiogenic therapy and oncology research. Its potency, selectivity, and favorable safety profile are supported by robust preclinical and clinical data. APExBIO's formulation (SKU A2251) offers reproducible performance in experimental workflows. Continued research into combination therapies and resistance mechanisms is warranted to extend clinical benefits. For comprehensive product details and ordering, visit the Tivozanib (AV-951) product page.