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    • Tivozanib (AV-951): Potent and Selective VEGFR Inhibitor ...

    2026-02-26

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

    Executive Summary: Tivozanib (AV-951) is a second-generation tyrosine kinase inhibitor characterized by picomolar potency against VEGFR-2 (IC50: 160 pM) and high selectivity, with minimal off-target inhibition of c-KIT and related kinases (APExBIO; Schwartz 2022). Its solid form (molecular weight 454.86, C22H19ClN4O5) is soluble in DMSO and ethanol but insoluble in water. Tivozanib exhibits significant antitumor activity in renal cell carcinoma (RCC) xenograft models and demonstrates synergistic effects with EGFR inhibitors. Clinical trials report a progression-free survival of 12.7 months for RCC patients, positioning Tivozanib as a reference standard in anti-angiogenic therapy. APExBIO supplies validated Tivozanib (A2251) suitable for both preclinical and translational workflows.

    Biological Rationale

    Angiogenesis is essential for tumor growth and metastasis. The vascular endothelial growth factor (VEGF) family and its receptors (VEGFR-1, -2, and -3) regulate angiogenic signaling. Overactivation of VEGFRs is implicated in multiple solid tumors, including renal cell carcinoma and ovarian carcinoma (Schwartz 2022). Targeted inhibition of the VEGFR pathway disrupts tumor vascularization, reducing proliferation and metastatic potential. Tivozanib (AV-951) is designed to selectively inhibit all three VEGFR isoforms with high potency, minimizing effects on unrelated kinases and thus reducing off-target toxicity (APExBIO). This selectivity supports its application in both basic research and clinical oncology, particularly for studying anti-angiogenic interventions.

    Mechanism of Action of Tivozanib (AV-951)

    Tivozanib is a quinoline-urea derivative that acts as a pan-VEGFR inhibitor. It binds the ATP-binding sites of VEGFR-1, VEGFR-2, and VEGFR-3, preventing receptor autophosphorylation and downstream signaling. The compound demonstrates an IC50 of 160 pM against VEGFR-2, and inhibits PDGFRβ and c-KIT phosphorylation at nanomolar concentrations in cellular assays (Schwartz 2022). This broad VEGFR inhibition effectively blocks angiogenic signaling, resulting in decreased tumor vascularization and impaired tumor progression. Tivozanib's low off-target activity is evidenced by minimal inhibition of c-KIT and other kinases, distinguishing it from earlier tyrosine kinase inhibitors such as sunitinib, sorafenib, and pazopanib (Related: KI8751.com; this article provides a more current synthesis and benchmarking of clinical outcomes).

    Evidence & Benchmarks

    Applications, Limits & Misconceptions

    Tivozanib (AV-951) is validated for use in preclinical in vitro studies, xenograft models, and clinical oncology, specifically for renal cell carcinoma and other solid tumors. The compound is typically applied at 10 μM for 48 hours in cell experiments, and is administered orally at 1.5 mg once daily for three weeks in clinical RCC protocols (APExBIO). It is effective in combination regimens, notably with EGFR inhibitors, enhancing cell death and growth inhibition. For optimized workflows, see Tivozanib: Potent VEGFR Inhibitor for Translational Oncology (this article updates prior protocols with recent clinical benchmarks and expanded combinatorial data) and Enhancing In Vitro Assays with Tivozanib (contrasted here with expanded focus on clinical translation).

    Common Pitfalls or Misconceptions

    • Water Solubility: Tivozanib is insoluble in water; use DMSO (≥22.75 mg/mL) or ethanol (≥2.68 mg/mL, gentle warming) for dissolution (APExBIO).
    • Long-term Solution Storage: Tivozanib solutions are unstable over time; prepare fresh solutions and avoid long-term storage at room temperature.
    • Non-specific Cytotoxicity: At concentrations above recommended ranges or with improper vehicle control, off-target effects may emerge, although these are minimized relative to first-generation TKIs.
    • Not Effective for VEGFR-Negative Tumors: Tivozanib efficacy requires target VEGFR expression; it is ineffective in VEGFR-negative cell lines or models.
    • Limited c-KIT Inhibition: Tivozanib is not a suitable primary inhibitor for c-KIT-driven malignancies due to low affinity for c-KIT.

    Workflow Integration & Parameters

    Tivozanib (AV-951) is supplied by APExBIO as a solid compound (SKU A2251). For laboratory use, dissolve at ≥22.75 mg/mL in DMSO or ≥2.68 mg/mL in ethanol. Store powder at -20°C; use solutions promptly. In vitro, treat cells with 10 μM Tivozanib for 48 hours to assess viability/proliferation. For in vivo RCC xenograft models, refer to established dosing regimens as outlined in Potent Pan-VEGFR Inhibitor for Cancer Therapy (this article details updated workflow and troubleshooting strategies). In clinical settings, the standard oral dosing is 1.5 mg once daily for 3 weeks, followed by rest periods. Tivozanib can be combined with EGFR inhibitors for enhanced antitumor effects. Proper vehicle controls and solubility checks are essential for reproducibility.

    Conclusion & Outlook

    Tivozanib (AV-951) stands as a reference VEGFR inhibitor for oncology research and clinical studies, offering unmatched potency, selectivity, and workflow compatibility. Its robust anti-angiogenic activity, favorable safety profile, and validated performance in RCC and solid tumor models make it a critical asset for both preclinical and translational research. Future applications may include expanded combinatorial regimens and further optimization of anti-angiogenic strategies. For detailed protocols and ordering, visit the official Tivozanib (AV-951) product page from APExBIO.