JNJ-7706621 443797-96-4

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Molecular Weight:

394.36 JNJ-7706621 is pan-CDK Inhibitor with the highest potency on CDK1/2 with IC50 of 9 nM/4 nM and showing >6-fold selectivity for CDK1/2 than CDK3/4/6. It also potently inhibits Aurora A/B and has no activity on Plk1 and Wee1.


Biological Activity


JNJ-7706621 also shows some inhibition to VEGF-R2, FGF-R2, and GSK3β,
with IC50 of 154-254 nM. JNJ-7706621 shows inhibitory effect on a panel
of human cancer cell types, including HeLa, HCT-116, SK-OV-3, PC3,
DU145, A375, MDA-MB-231, MES-SA, and MES-SA/Dx5, with IC50 of 112-514
nM, independent of p53, retinoblastoma, or P-glycoprotein status.
JNJ-7706621 is several-fold less potent at inhibiting growth of normal
cell types, including MRC-5, HASMC, HUVEC, and HMVEC, with IC50 of
3.67-5.42 μM.


In HeLa or U937 cells, JNJ-7706621 (0.5-3 μM) delays exit
from G1, arrests cells in G2-M, induces endoreduplication, activates
Apoptosis, and reduces colony formation. In a HeLa cell line,
incremental treatment with increasing concentrations of JNJ-7706621
leads to a 16-fold resistance, which may be mediated by ABCG2.


In mouse xenograft model of A375 melanoma human tumor, JNJ-7706621 (100 or 125 mg/kg) causes tumor regression.


Protocol(Only for Reference)


Kinase Assay: [1]

In vitro kinase assay for CDK1 and Aurora kinases

For CDK1 kinase activity, a method is developed using the CDK1/cyclin B complex purified from baculovirus to phosphorylate a biotinylated peptide substrate containing the consensus phosphorylation site for histone H1, which is phosphorylated in vivo by CDK1. Inhibition of CDK1 activity is measured by observing a reduced amount of 33P-γ-ATP incorporation into the immobilized substrate in streptavidin-coated 96-well scintillating microplates. CDK1 enzyme is diluted in 50 mM Tris-HCl (pH 8), 10 mM MgCl2, 0.1 mM Na3VO 4, 1 mM DTT, 1% DMSO, 0.25 μM peptide, 0.1 μCi per well 33P-γ-ATP, and 5 μM ATP in the presence or absence of various concentrations of JNJ-7706621 and incubated at 30 °C for 1 hour. The reaction is terminated by washing with PBS containing 100 mM EDTA and plates are counted in a scintillation counter. Linear regression analysis of the percent inhibition by JNJ-7706621 is used to determine IC50. The Aurora kinase assays are done with 10 μM ATP and a peptide containing a dual repeat of the kemptide phosphorylation motif.

Cell Assay: [3]

Cell lines	HeLa, HCT-116, A375, SK-OV-3, MDA-MB-231, and PC-3 cells
Concentrations	1 nM - 10 μM, dissolved in DMSO
Incubation Time	48 hours
Method	The ability of JNJ-7706621 to inhibit the proliferation of cell growth is determined by measuring incorporation of 14C-labelled thymidine into newly synthesized DNA within the cells. Cells are trypsinized and counted and 3-8 × 103 cells are added to each well of a 96-well CytoStar tissue culture treated scintillating microplate in complete medium in a volume of 100 μL. Cells are incubated for 24 hours in complete medium at 37 °C in an atmosphere containing 5% CO2. Next, 1 μL of JNJ-7706621 is added to the wells of the plate. Cells are incubated for 24 more hours. Methyl 14C-thymidine 56 mCi/mmol is diluted in complete medium and 0.2 μCi/well is added to each well of the CytoStar plate in a volume of 20 μL. The plate is incubated for 24 hours at 37 °C in JNJ-7706621 plus 14C-thymidine. The contents of the plate are discarded and the plate is washed twice with 200 μL PBS. 200 μL of PBS is added to each well. The top of the plate is sealed with a transparent plate sealer and a white plate backing sealer is applied to the bottom of the plate. The degree of methyl 14C-thymidine incorporation is quantified on a Packard Top Count.

Animal Study: [1]

Animal Models	Mouse xenograft model of A375 cells
Formulation	Dissolved in 0.5% methylcellulose containing 0.1% polysorbate 80 in sterile water.
Dosages	100 or 125 mg/kg
Administration	Orally or by intraperitoneal injection injection
Solubility	0.5% methylcellulose/0.2% Tween 80, 14 mg/mL
* 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.

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)	394.36
Formula	C15H12F2N6O3S
CAS No.	443797-96-4

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

Solubility (25°C) *	In vitro	DMSO	79 mg/mL (200.32 mM)
		Water	<1 mg/mL (
		Ethanol	<1 mg/mL (
	In vivo	0.5% methylcellulose/0.2% Tween 80	14 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	4-[[5-amino-1-(2,6-difluorobenzoyl)-1H-1,2,4-triazol-3-yl]amino]-benzenesulfonamide

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