Axitinib

Names

[ CAS No. ]:
319460-85-0

[ Name ]:
Axitinib

[Synonym ]:
N-Methyl-2-({3-[(E)-2-(2-pyridinyl)vinyl]-1H-indazol-6-yl}sulfanyl)benzamide
Benzamide, N-methyl-2-[[3-[(E)-2-(2-pyridinyl)ethenyl]-1H-indazol-6-yl]thio]-
UNII-C9LVQ0YUXG
Inlyta
Benzamide, N-methyl-2-[[3-[(1E)-2-(2-pyridinyl)ethenyl]-1H-indazol-6-yl]thio]-
10mg
Axitinib (usan)
N-Methyl-2-({3-[(E)-2-(pyridin-2-yl)vinyl]-1H-indazol-6-yl}sulfanyl)benzamide
AG-013736 N-Methyl-2-((3-((1E)-2-(pyridin-2-yl)ethenyl)-1H-indazol-6-yl)sulfanyl)benzamide
Axtinib
AVERMECTINB
Axitinib
N-methyl-2-({3-[(E)-2-(pyridin-2-yl)ethenyl]-1H-indazol-6-yl}sulfanyl)benzamide
[14C]-Axitinib

Biological Activity

[Description]:

Axitinib is a multi-targeted tyrosine kinase inhibitor with IC50s of 0.1, 0.2, 0.1-0.3, 1.6 nM for VEGFR1, VEGFR2, VEGFR3 and PDGFRβ, respectively.

[Related Catalog]:

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> PDGFR

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> VEGFR

Research Areas >> Cancer

[Target]

VEGFR1:0.1 nM (IC50)

VEGFR2:0.2 nM (IC50)

VEGFR3:0.1 nM (IC50)

PDGFRβ:1.6 nM (IC50)

[In Vitro]

Axitinib (AG-013736) is a potent and selective inhibitor of VEGFR 1 to 3. In transfected or endogenous RTK-expressing cells, Axitinib potently blocks growth factor-stimulated phosphorylation of VEGFR-2 and VEGFR-3 with average IC50 values of 0.2 and 0.1 to 0.3 nM, respectively. Cellular activity against VEGFR-1 is 1.2 nM (measured in the presence of 2.3% bovine serum albumin), equivalent to an absolute IC50 of ~0.1 nM, based on protein binding of Axitinib. The potency against murine VEGFR-2 (Flk-1) in Flk-1-transfected NIH-3T3 cells is 0.18 nM, similar to that of its human homologue. Axitinib shows ~8- to 25-fold higher IC50 against the closely related type III and V family RTKs, including PDGFR-β (1.6 nM), KIT (1.7 nM), and PDGFR-α (5 nM); nanomolar concentrations of Axitinib blocks PDGF BB-mediated human glioma U87MG cell (PDGFR-β-positive) migration but not proliferation[2].

[In Vivo]

A single oral dose of Axitinib (100 mg/kg) markedly suppresses murine VEGFR-2 phosphorylation for up to 7 h compared with control tumors. Axitinib rapidly inhibits VEGF-induced vascular permeability in the skin of mice; the inhibition is dose-dependent and directly correlated with drug concentration in mice. Pharmacokinetic/pharmacodynamic analysis indicate an unbound EC50 of 0.46 nM. Similar inhibitory effects are also shown in the skin of MV522 tumor-bearing mice without exogenous VEGF-A stimulation. Axitinib inhibits the growth of human xenograft tumors in mice. Axitinib produces dose-dependent growth delay regardless of initial tumor size, model type, or implant site[2].

[Cell Assay]

Endothelial or tumor cells are starved for 18 h in the presence of either 1% FBS (HUVEC) or 0.1% FBS (tumor cells). Axitinib is added and cells are incubated for 45 min at 37°C in the presence of 1 mM Na3VO4. The appropriate growth factor is added to the cells, and after 5 min, cells are rinsed with cold PBS and lysed in the lysis buffer and a protease inhibitor cocktail. The lysates are incubated with immunoprecipitation antibodies for the intended proteins overnight at 4°C. Antibody complexes are conjugated to protein A beads and supernatants are separated by SDS-PAGE[2].

[Animal admin]

Mice and Rats[2] Mice with M24met xenograft tumors (400-600 mm3) are administered with a single dose of Axitinib or the control (0.5% carboxymethylcellulose/H2O). Blood and tumor tissue samples are collected for pharmacokinetic and VEGFR-2 measurements. Total protein concentrations in tumor tissues are determined using the Bradford colorimetric assay. Six-day-old Sprague-Dawley rats are given two i.p. injections of Axitinib (30 mg/kg ). Animals are sacrificed, retinas are collected and lysed, and immunoprecipitation/immunoblotting experiments are done. ECL-Plus is used for detection and densitometry analysis is done using the Alpha Imager 8800.

[References]

[1]. Fenton BM, et al. The addition of AG-013736 to rractionated radiation improves tumor response without functionally normalizing the tumor vasculature. Cancer Res. 2007 Oct 15;67(20):9921-8.

[2]. Hu-Lowe DD, et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res. 2008 Nov 15;14(22):7272-83

[3]. Allen E, et al. Metabolic Symbiosis Enables Adaptive Resistance to Anti-angiogenic Therapy that Is Dependent on mTOR Signaling. Cell Rep. 2016 May 10;15(6):1144-60.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.4±0.1 g/cm3

[ Boiling Point ]:
668.9±55.0 °C at 760 mmHg

[ Melting Point ]:
213-215ºC

[ Molecular Formula ]:
C₂₂H₁₈N₄OS

[ Molecular Weight ]:
386.470

[ Flash Point ]:
358.3±31.5 °C

[ Exact Mass ]:
386.120117

[ PSA ]:
95.97000

[ LogP ]:
4.15

[ Vapour Pressure ]:
0.0±2.0 mmHg at 25°C

[ Index of Refraction ]:
1.728

[ Storage condition ]:
-20°C Freezer

MSDS

Click to get detail MSDS

Safety Information

[ Symbol ]:

GHS07, GHS09

[ Signal Word ]:
Warning

[ Hazard Statements ]:
H302-H400

[ Precautionary Statements ]:
P273

[ Hazard Codes ]:
Xn,N

[ Risk Phrases ]:
22-50/53

[ Safety Phrases ]:
60-61

[ RIDADR ]:
UN 3077 9 / PGIII

[ HS Code ]:
2933990090

Precursor & DownStream

Precursor

DownStream

Customs

[ HS Code ]: 2933990090

[ Summary ]:
2933990090. heterocyclic compounds with nitrogen hetero-atom(s) only. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0%

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