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Tivozanib, also known as AV-951 and KRN-951, is an orally active, ATP-competitive, small-molecule, quinoline-urea derivative. Tivozanib is a pan-VEGFR tyrosine kinase inhibitor.

In vitro: Tivozanib markedly inhibited the ligand-induced phosphorylation of VEGFR1\2 and 3 with the IC50 value of 30 nM\6.5 nM and 15 nM, respectively. Tivozanib also exihibited inhibitory effects on PDGFR and c-Ki with the IC50 value of 1.72 and 1.63 nmol/L, respectively. Tivozanib showed little activity against FGFR-1, Flt3, c-Met, EGFR and IGF-1R [1]. Tivozanib blocked VEGF-dependent activation of mitogen-activated protein kinases and proliferation of endothelial cells. It also inhibited VEGF-mediated migration of human umbilical vein endothelial cells [1].

In vivo: In tumor xenografts athymic rat model, p.o. administration of tivozanib decreased the micro vessel density and suppressed VEGFR2 phosphorylation levels, especially at a concentration of 1mg/kg. Tivozanib almost completely inhibited tumor xenografts growth (TGI > 85%) in athymic rats. Tivozanib displayed antitumor activity against various human tumor xenografts, such as lung, breast, colon, pancreas, ovarian and prostate cancer.[1]. In rat peritoneal disseminated tumor model, tivozanib prolonged the survival of the tumor-bearing rats with the MST of 53.5 days [2].

Clinical trials: Tivozanib has entered phase III clinical trials in patients with advanced renal cell carcinoma. Tivozanib improved progression-free survival (PFS), but not overall survival (OS). The most common adverse events were hypertension and dysphonia [3]. In patients with refractory, metastatic colorectal cancer, tivozanib has entered Multicenter phase II study [4].

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