GNF-2 778270-11-4

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Molecular Weight:

374.32 GNF-2 is a highly selective non-ATP competitive inhibitor of Bcr-Abl, shows no activity to Flt3-ITD, Tel-PDGFR, TPR-MET and Tel-JAK1 transformed tumor cells.


Biological Activity


GNF-2 causes a dose-dependent growth inhibition of the Bcr-abl–positive
cell lines with IC50 values of 273 nM (K562) and 268 nM (SUP-B15). GNF-2
inhibits the growth of Ba/F3.p210E255V and Ba/F3.p185Y253H cells with IC50 values of 268 nM and 194 nM respectively. GNF-2 (1 μM)
induces Apoptosis of Ba/F3.p210 cells as well as Ba/F3.p210E255V cells. GNF-2 inhibits the cellular tyrosine phosphorylation of Bcr-abl
in a dose-dependent manner with IC50 of 267 nM. GNF-2 (1 μM) induces a
significant decrease in the levels of phospho-Stat5 in Ba/F3.p210 cells.


GNF-2 binds to the myristic binding pocket of Bcr-abl. GNF-2 inhibits the kinase activity of non-myristoylated c-Abl more
potently than that of myristoylated c-Abl by binding to the
myristate-binding pocket in the C-lobe of the kinase domain. GNF-2 (10
μM) requires BCR and/or the c-Abl SH3 and/or SH2 domains to inhibit
BCR-Abl-dependent cell proliferation. GNF-2, but not a methylated GNF-2
analog, binds c-Abl in cellular extracts derived from 3T3 fibroblasts.
GNF-2 (10 μM), in a dose-dependent manner, clearly inhibits tyrosine
phosphorylation of CrkII.


GNF-2 inhibits the phosphorylation of CrkII in
c-AblG2A-expressing cells with IC50 of 0.051 μM. GNF-2
binds in an extended conformation in the myristate pocket with the
CF3-group buried at the same depth as the final two carbons of the
myristate ligand. GNF-2 (10 µM) combined with imatinib (1 µM) reduces
the number of resistant clones to 1 µM imatinib by at least 90%. GNF-2 inhibits the auto-phosphorylation and proliferation of BafF3
cells expressing p210Bcr–Abl and p210Bcr–Abl mutants. GNF-2 (8 nM) in
combination with GNF-5 (20 nM) results in additive effects with respect
to inhibition of the Abl64–515 kinase activity.


Protocol(Only for Reference)


Kinase Assay: [2]

Binding assay

Recombinant Proteins (100 nM for each construct) or immunoprecipitated proteins are diluted in kinase buffer (20 mM HEPES (pH 7.4), 50 mM KCl, 0.1% CHAPS, 30 mM MgCl2, 2 mM MnCl2, 1 mM DTT, and 1% glycerol). Aliquots of the diluted proteins are preincubated with either DMSO or compounds for 30 min at room temperature and then added to K-LISA PTK EAY reaction plates. The kinase reaction is initiated by adding 0.1 mM ATP and is allowed to proceed for 30 min at room temperature. The phosphorylation of GST-Abltide is monitored by SDS-PAGE and phosphorimaging analysis or autoradiography.

Cell Assay: [1]

Cell lines	Ba/F3.p210, Ba/F3.p210E255V and Ba/F3.p185Y253H cells
Concentrations	~10 μM
Incubation Time	48 hours
Method	Cells (0.3-0.6 × 106 per mL) are plated in duplicate or triplicate in 96-well plates containing increasing GNF-2 concentrations (5 nM–10 μM). After incubation at 37 ℃ in 5% CO2 for 48 hours, the effect of GNF-2 on cell viability is determined by the MTT colorimetric dye reduction method. Inhibition of cell proliferation is calculated as a percentage of growth of DMSO-treated cells, and IC50 values are determined with Microsoft Excel XLfit3.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Baboon	Dog	Monkey	Rabbit	Guinea pig	Rat	Hamster	Mouse
Weight (kg)	12	10	3	1.8	0.4	0.15	0.08	0.02
Body Surface Area (m2)	0.6	0.5	0.24	0.15	0.05	0.025	0.02	0.007
Km factor	20	20	12	12	8	6	5	3

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×	mouse Km(3)	= 11.2 mg/kg
	rat Km(6)

Chemical Information

Molecular Weight (MW)	374.32
Formula	C18H13F3N4O2
CAS No.	778270-11-4

Storage	3 years -20℃Powder
	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms

Solubility (25°C) *	In vitro	DMSO	74 mg/mL (197.69 mM)
		Water	<1 mg/mL (
		Ethanol	<1 mg/mL (
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Name	Benzamide, 3-[6-[[4-(trifluoromethoxy)phenyl]amino]-4-pyrimidinyl]-

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Product Categories : Angiogenesis > Bcr-Abl Inhibitor