1. Materials information
Names
| Name |
axitinib
|
| Synonym |
More Synonyms
|
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.
|
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 |
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 |
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% |
2. Packaging of materials
For powders: normal is 25kgs/Drum or bag, or larger/smaller package as request.
For liquids: normal 25kgs/drum, 180-300kgs/bucket, or IBC, determined by the nature of the product.
Or smaller package 1kg/bottle, 10kgs/bottle as request.
3. Shipping & Delivery
Provide door to door service
Suitable for goods under 50kg
Delivery: 3-7 days
Cost: low cost
Provide airport to airport service
Suitable for goods over 50kg
Delivery: 3-14 days
Cost: high cost
Provide seaport to seaport service
Suitable for goods over 100kg
Delivery: 2-45 days
Cost: low cost
4. Contact information
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China
CAS#:100-69-6
CAS#:885126-34-1
