There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic
USD 100+
Accessible (Haz class 3, 4, 5 or 8), International
Bcr-Abl fusion protein is formed as a result of a chromosomal translocation event forming the Philadelphia chromosome that fuses the breakpoint cluster region (BCR) gene to the N-terminus of the Abelson tyrosine kinase (ABL1) gene, which cause Chronic myelogenous leukemia(CML)[3]. GNF-5 is a highly selective non-ATP competitive inhibitor of Bcr-Abl with IC50 value of 0.22μM. GNF-5 alters conformation and hydrogen exchange in the peptide near the ATP-site. In vitro, GNF-5 exhibited inhibition of wild-type Bcr-Abl transformed Ba/F3 cells. Treatment with 10μM GNF-5 significantly inhibited the proliferation of T315I Bcr-Abl Ba/f3 cells[1]. Treatment MDA-MB-231 cells with 10μM GNF-5 decreased in active, matrix-degrading invadopodia, but did not affect cell proliferation. In addition, GNF-5 affected cortactin tyrosine phosphorylation and reduced actin barbed end generation in MDA-MB-231 cells[4]. In vivo, oral administered GNF-5 at 75mg/kg twice daily significantly extended survival of the mice transplanted with T315I Bcr-Abl transduced bone marrow[1].Treatment MDA-MB-231 cells xenograft mouse model with GNF-5 at dose of 100mg/kg once daily via oral gavage for 4 weeks suppressed matrix metalloproteinase (MMP) activity, tumor cell invasion, and consequent spontaneous metastasis to lungs[4].
作用机制
GNF-5 binds to the myristate pocket near the C-terminus of the ABL kinase domain and transmits structural changes to the ATP binding site[4].
GNF-5 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human airway smooth muscle (HASM) cells
5 µM
1 hour or 24 hours
To evaluate the inhibitory effect of GNF-5 on c-Abl, it was found that GNF-5 reduced the number of cells undergoing cytokinesis, increased the quantity of cells in metaphase/anaphase, and increased the number of multinucleate cells
Am J Respir Cell Mol Biol. 2014 Jun;50(6):1076-83.
Mouse tracheal rings
10 µM
10 minutes
To evaluate the inhibitory effect of GNF-5 on acetylcholine-induced contraction of tracheal rings, results showed that GNF-5 significantly attenuated the contraction of tracheal rings.
Respir Res. 2013 Oct 11;14(1):105.
Human ASM cells
10 µM
10 minutes
To assess the cooperative effects of β-agonists and c-Abl inhibitors on ASM contraction, results showed that GNF-5 and β-agonist ISO combined significantly enhanced ASM relaxation.
FASEB J. 2021 Jul;35(7):e21674.
Ba/F3 cells
2 µM
Combinations of GNF-5 and nilotinib inhibited T315I Bcr-Abl-dependent cell growth, showing moderate synergy.
Nature. 2010 Jan 28;463(7280):501-6.
GNF-5 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
BALB/c mice
OVA-induced asthma model
Intranasal administration
10 mg/kg
1 hour before and 5 hours after each OVA challenge, lasting for three weeks
To evaluate the inhibitory effect of GNF-5 on airway resistance and airway smooth muscle hyperplasia in the OVA-induced asthma model, results showed that GNF-5 significantly inhibited the increase in airway resistance and smooth muscle growth.
Respir Res. 2013 Oct 11;14(1):105.
Mice
Murine precision cut lung slices model
In vitro treatment
10 μM
20 minutes
To assess the cooperative effects of GNF-5 and β-agonist ISO on ASM contraction, results showed that GNF-5 and ISO combined significantly enhanced ASM relaxation.
FASEB J. 2021 Jul;35(7):e21674.
Mice
T315I Bcr-Abl bone marrow transplantation model
Oral
75 mg/kg
Twice daily for 15 days
The combination of GNF-5 with nilotinib showed significant efficacy in the T315I Bcr-Abl bone marrow transplantation model, normalizing blood cell counts and spleen size, and significantly extending the survival of mice.
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