Tivozanib (hydrate)

Description

Tivozanib is an orally available, selective VEGFR inhibitor with IC₅₀ values of 0.21, 0.16, and 0.24 nM for VEGFR1, VEGFR2, and VEGFR3, respectively. It can also inhibit c-Kit and PDGFRβ with IC₅₀ values of 1.63 and 1.72 nM, respectively. When administered to athymic rats, tivozanib was shown to decrease the microvessel density within tumor xenografts and attenuate VEGFR2 phosphorylation levels in tumor endothelium. It also displays antitumor activity against a wide variety of human tumor xenografts, including lung, breast, colon, ovarian, pancreas, and prostate cancer.

Uses

Tivozanib hydrate (AV-951 hydrate; KRN951 hydrate) is the hydrate form of Tivozanib (HY-10977). Tivozanib hydrate is a selective, orally active inhibitor for vascular endothelial growth factor receptor (VEGFR)-1, 2 3, with IC50s of 30, 6.5 and 15 nM, respectively. Tivozanib hydrate exhibits antitumor efficacy[1].

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].

IC 50

VEGFR2: 6.5 nM (IC₅₀); VEGFR3: 15 nM (IC₅₀); VEGFR1: 30 nM (IC₅₀)

References

[1]. nakamura k, taguchi e, miura t, et al. krn951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties[j]. cancer research, 2006, 66(18): 9134-9142.
[2]. taguchi e, nakamura k, miura t, et al. anti‐tumor activity and tumor vessel normalization by the vascular endothelial growth factor receptor tyrosine kinase inhibitor krn951 in a rat peritoneal disseminated tumor model[j]. cancer science, 2008, 99(3): 623-630.
[3]. motzer r j, nosov d, eisen t, et al. tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase iii trial[j]. journal of clinical oncology, 2013, 31(30): 3791-3799.
[4]. wolpin b m, ng k, zhu a x, et al. multicenter phase ii study of tivozanib (av-951) and everolimus (rad001) for patients with refractory, metastatic colorectal cancer[j]. the oncologist, 2013, 18(4): 377-378.

Raw materials

Preparation Products