JNJ-7706621

Information	JNJ-7706621 is a novel, potent, and broad-spectrum inhibitor of CDK and Aurora kinases including CDK1/Cyclin B, CDK2/Cyclin A, CDK2/Cyclin E, Aurora-A and Aurora-B with IC50 of 9 nM, 4 nM, 3 nM and 11 nM, respectively.
Targets	CDK1/Cyclin B	CDK2/Cyclin A	CDK2/Cyclin E	Aurora-A	Aurora-B
IC50	9 nM	4 nM	3 nM	11 nM	15 nM ^[1]
In vitro	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. ^[1] 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. ^[2]
In vivo	In mouse xenograft model of A375 melanoma human tumor, JNJ-7706621 (100 or 125 mg/kg) causes tumor regression. ^[3]
Clinical Trials
Features	JNJ-7706621 is a broad-spectrum inhibitor.

Information

JNJ-7706621 is a novel, potent, and broad-spectrum inhibitor of CDK and Aurora kinases including CDK1/Cyclin B, CDK2/Cyclin A, CDK2/Cyclin E, Aurora-A and Aurora-B with IC50 of 9 nM, 4 nM, 3 nM and 11 nM, respectively.

Targets

CDK1/Cyclin B

CDK2/Cyclin A

CDK2/Cyclin E

Aurora-A

Aurora-B

IC50

9 nM

4 nM

3 nM

11 nM

15 nM ^[1]

In vitro

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. ^[1] 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. ^[2]

In vivo

In mouse xenograft model of A375 melanoma human tumor, JNJ-7706621 (100 or 125 mg/kg) causes tumor regression. ^[3]

Clinical Trials

Features

JNJ-7706621 is a broad-spectrum inhibitor.

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 ℃ 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 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 ℃ 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℃ 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.

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 ℃ 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℃ 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 Models:	Mouse xenograft model of A375 cells
Formulation:	Dissolved in 0.5% methylcellulose containing 0.1% polysorbate 80 in sterile water.
Dosages:	Dissolved in 0.5% methylcellulose containing 0.1% polysorbate 80 in sterile water.
Administration:	Orally or by intraperitoneal injection injection

Animal Models:

Mouse xenograft model of A375 cells

Formulation:

Dissolved in 0.5% methylcellulose containing 0.1% polysorbate 80 in sterile water.

Dosages:

Dissolved in 0.5% methylcellulose containing 0.1% polysorbate 80 in sterile water.

Administration:

Orally or by intraperitoneal injection injection

Molecular Weight (WM):	394.36
Formula:	C₁₅H₁₂F₂N₆O₃S
CAS No.:	443797-96-4
Synonyms:	N/A

Molecular Weight (WM):

394.36

Formula:

C₁₅H₁₂F₂N₆O₃S

CAS No.:

443797-96-4

Synonyms:

N/A

Dissolve in (25°C):	DMSO ≥79mg/mL
	Water <1mg/mL
	Ethanol ≥3mg/mL
Storage:	2 years-20°CPowder
	1 week-4°Cin DMSO
	1 month-80°in DMSO

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Biological Activity

Protocol (Only for Reference)

Kinase Assay: [1]

Cell Assay: [3]

Animal Study:[1]

References

Chemical Information

Quality Control & MSDS

Research Area

Related Inhibitors

Secondary Antibodies

Loading Control Antibodies

Recommended Screening Libraries

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Kinase Assay: ^[1]

Cell Assay: ^[3]

Animal Study:^[1]

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