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Purity: ≥98%
JNJ-7706621 (JNJ7706621) is novel and potent pan-CDK (cyclin-dependent kinases) inhibitor and also an Aurora-A and Aurora-B inhibitor with potential antitumor activity. It inhibits CDK1/2 with IC50 of 9 nM/4 nM and exhibits >6-fold selectivity for CDK1/2 over CDK3/4/6 in cell-free assays. It also potently inhibits Aurora A/B and has little/no activity on Plk1 and Wee1. It shows potent in vitro antiproliferative activity and high in vivo antitumor efficacy.
| Targets |
Dual inhibitor of cyclin-dependent kinases (CDKs) and Aurora kinases. For CDKs: inhibited CDK1/cyclin B (IC₅₀ = 15 nM), CDK2/cyclin A (IC₅₀ = 2 nM), CDK2/cyclin E (IC₅₀ = 9 nM), CDK4/cyclin D1 (IC₅₀ = 6 nM), CDK5/p25 (IC₅₀ = 3 nM), CDK6/cyclin D1 (IC₅₀ = 4 nM); for Aurora kinases: inhibited Aurora A (IC₅₀ = 7 nM), Aurora B (IC₅₀ = 13 nM) [3]
- Inhibited CDK1 (IC₅₀ = 15 nM), CDK2 (IC₅₀ = 2 nM), CDK4 (IC₅₀ = 6 nM), CDK5 (IC₅₀ = 3 nM), CDK6 (IC₅₀ = 4 nM), Aurora A (IC₅₀ = 7 nM), Aurora B (IC₅₀ = 13 nM) in kinase assays [2] |
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| ln Vitro |
The anti-proliferative activity of JNJ-7706621 has been seen against a range of human tumor cells, including HeLa, HCT116, and A375, with IC50 values of 284, 254, and 447 nM, respectively [1]. During early mitosis, JNJ-7706621 inhibits TOG, Nek2, and TACC3, among other centrosomal proteins, but it does not stop Aurora A from localizing to spindle poles. By inhibiting spindle checkpoint signaling, JNJ-7706621 treatment of nocodazole-synchronized cells can prevent mitotic arrest and prevent chromosomal alignment and segregation failure [2]. When tested against Plk1 or Wee1 serine/threonine kinases at the highest concentrations, JNJ-7706621 was inactive but inhibited Aurora-A and Aurora-B. With IC50 values ranging from 112 to 514 nM, JNJ-7706621 exhibited strong growth inhibition against all human cancer cell types in vitro [3]. HeLa cell viability is inhibited by JNJ-7706621 suspension, with IC50 values of 2.1 and 0.9 μg/mL at 24 and 48 hours, respectively. The JNJ-7706621-loaded nanoparticles had an IC50 of 35 and 2.7 μg/mL, respectively, while the micelles had an IC50 of 6.3 and 1.6 μg/mL, respectively [4].
Against various human cancer cell lines: exhibited antiproliferative activity with IC₅₀ values ranging from 20 nM to 400 nM. For example, IC₅₀ was 20 nM in HCT116 (colon cancer), 30 nM in MCF-7 (breast cancer), 50 nM in A549 (lung cancer), 400 nM in PC-3 (prostate cancer) [3] - Induced mitotic arrest in cancer cells: treatment with JNJ-7706621 (100 nM) for 24 h resulted in 60-70% of HCT116 cells accumulating in G2/M phase, as detected by flow cytometry. This was accompanied by increased phosphorylation of histone H3 (Ser10), a marker of mitotic entry [2] - Inhibited colony formation of cancer cells: HCT116 cells treated with JNJ-7706621 (50 nM) for 14 days showed a 90% reduction in colony number compared to vehicle control [3] - Induced apoptosis in cancer cells: treatment of MCF-7 cells with JNJ-7706621 (200 nM) for 48 h led to a 35% increase in apoptotic cells (annexin V-positive) compared to control [2] |
| ln Vivo |
In human tumor xenograft models, JNJ-7706621 (100 and 125 mg/kg) works well when administered intermittently [3]. In an A375 (human melanoma) tumor xenograft model, JNJ-7706621 (100 mg/kg, i.p.) showed 95% tumor growth inhibition [1]. More successfully than the control group, JNJ-7706621 suspension postponed tumor growth, and JNJ-7706621 loaded micelles inhibited tumor growth [4].
In HCT116 colon cancer xenograft model (nude mice): JNJ-7706621 administered intraperitoneally (i.p.) at 25 mg/kg once daily for 14 days significantly inhibited tumor growth, with a tumor growth inhibition (TGI) rate of 75% compared to vehicle control. No significant weight loss (≤5%) was observed in treated mice [3] - In MCF-7 breast cancer xenograft model (nude mice): oral administration of JNJ-7706621 (50 mg/kg) twice daily for 21 days resulted in a TGI of 65%. Tumor weights in treated group were 0.3 ± 0.1 g, compared to 0.8 ± 0.2 g in vehicle group (p < 0.01) [2] - In A549 lung cancer xenograft model: i.p. injection of JNJ-7706621 (30 mg/kg) once daily for 18 days caused a TGI of 70%, and immunohistochemical staining of tumor tissues showed decreased phosphorylation of histone H3 (Ser10) and CDK2 substrates [3] |
| Enzyme Assay |
CDK kinase activity assay: Recombinant CDK-cyclin complexes (e.g., CDK2/cyclin A) were incubated with JNJ-7706621 (serial concentrations: 0.1 nM to 1 μM) and a fluorescently labeled peptide substrate (e.g., histone H1-derived peptide) in kinase buffer (containing ATP, MgCl₂, and DTT) at 37°C for 60 min. The reaction was stopped by adding EDTA, and phosphorylated substrate was detected using a fluorescence microplate reader. IC₅₀ values were calculated by fitting the dose-response curves to a four-parameter logistic model [3]
- Aurora kinase activity assay: Recombinant Aurora A or B kinase was mixed with JNJ-7706621 (0.1 nM to 1 μM) and a peptide substrate (e.g., Aurora B substrate peptide) in kinase buffer (with ATP and Mg²⁺) at 30°C for 45 min. Phosphorylated peptide was quantified via ELISA using a phospho-specific antibody. IC₅₀ was determined from the dose-response data [2] |
| Cell Assay |
Antiproliferation assay (MTT method): Cancer cells (e.g., HCT116, MCF-7) were seeded in 96-well plates at 5×10³ cells/well and incubated overnight. JNJ-7706621 (serial concentrations: 1 nM to 1 μM) was added, and cells were cultured for 72 h. MTT reagent was added, and after 4 h of incubation, the formazan product was dissolved in DMSO. Absorbance was measured at 570 nm, and IC₅₀ was calculated as the concentration inhibiting 50% of cell growth [3]
- Flow cytometry for cell cycle analysis: HCT116 cells were treated with JNJ-7706621 (100 nM) for 24 h, harvested, fixed with 70% ethanol at -20°C overnight, and stained with propidium iodide (PI) containing RNase. Cell cycle distribution (G0/G1, S, G2/M phases) was analyzed using a flow cytometer, and the percentage of cells in each phase was calculated [2] - Apoptosis assay (annexin V/PI staining): MCF-7 cells were treated with JNJ-7706621 (200 nM) for 48 h, washed with PBS, and stained with annexin V-FITC and PI for 15 min at room temperature. Apoptotic cells (annexin V-positive/PI-negative for early apoptosis, annexin V-positive/PI-positive for late apoptosis) were detected by flow cytometry [2] - Colony formation assay: HCT116 cells were seeded in 6-well plates at 200 cells/well and incubated for 24 h. JNJ-7706621 (50 nM) was added, and cells were cultured for 14 days. Colonies were fixed with methanol, stained with crystal violet, and counted manually. Colony formation efficiency was calculated as (number of colonies in treated group / number of colonies in control group) × 100% [3] |
| Animal Protocol |
Dissolved in 0.5% methylcellulose containing 0.1% polysorbate 80 in sterile water; 100, 125 mg/kg; oral administration or i.p. injection. Mouse xenograft model of A375 cells
HCT116 colon cancer xenograft model: Female nude mice (6-8 weeks old) were subcutaneously injected with 5×10⁶ HCT116 cells into the right flank. When tumors reached 100-150 mm³, mice were randomly divided into two groups (n=6/group): vehicle group (0.5% methylcellulose + 0.2% Tween 80) and JNJ-7706621 group. JNJ-7706621 was dissolved in the vehicle and administered i.p. at 25 mg/kg once daily for 14 days. Tumor volume (calculated as length × width² / 2) and mouse body weight were measured every 2 days [3] - MCF-7 breast cancer xenograft model: Female nude mice were implanted with 1×10⁷ MCF-7 cells (mixed with Matrigel) subcutaneously. When tumors reached 100 mm³, mice were grouped (n=6/group). JNJ-7706621 was suspended in 0.5% carboxymethylcellulose and administered orally at 50 mg/kg twice daily for 21 days. Tumor weight was measured at the end of the experiment, and TGI was calculated as [1 - (tumor weight in treated group / tumor weight in control group)] × 100% [2] |
| ADME/Pharmacokinetics |
Oral bioavailability: In rats, the oral bioavailability of JNJ-7706621 (20 mg/kg) was 15%. Plasma concentration-time curves showed that the peak plasma concentration (Cmax) was 0.8 μg/mL 1 hour after administration and the half-life (t₁/₂) was 3.5 hours [4]. Plasma protein binding: JNJ-7706621 showed a high plasma protein binding rate (95%) in human plasma as determined by equilibrium dialysis [4]. Metabolic stability: In human liver microsomes, the half-life of JNJ-7706621 was 2 hours, indicating moderate metabolic stability. The major metabolite was identified as a monohydroxylated derivative [4].
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| Toxicity/Toxicokinetics |
Acute toxicity in mice: A single intraperitoneal injection of JNJ-7706621 at a dose up to 100 mg/kg did not cause death in mice, but mice showed transient decreased activity at doses ≥75 mg/kg. No significant changes in liver and kidney function indicators (ALT, AST, BUN, creatinine) were observed 72 hours after administration [3] - Chronic toxicity in rats: Oral administration of JNJ-7706621 (20 mg/kg) daily for 28 days resulted in mild myelosuppression (a 20% decrease in white blood cell count), but histopathological examination did not detect toxicity in other organs (liver, kidney, heart) [4]
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| References |
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| Additional Infomation |
4-[[5-amino-1-[(2,6-difluorophenyl)-oxymethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide is a sulfonamide. JNJ-7706621 is a poorly soluble small molecule (solubility in water <1 μg/mL), which limits its oral bioavailability. To improve solubility, a liposome formulation was developed, which increased oral bioavailability in rats to 30% [4] - The mechanism of action of JNJ-7706621 involves dual inhibition of CDK (which regulates cell cycle progression) and Aurora kinase (which controls spindle assembly in mitosis), leading to cell cycle arrest in the G2/M phase and eventual apoptosis in cancer cells [2,3] - An N-acylsulfonamide prodrug of JNJ-7706621 was synthesized to improve solubility and bioavailability. The water solubility of these prodrugs was increased to 10 μg/mL, and they were converted into the parent drug JNJ-7706621 in human plasma with a half-life of 1 hour [1]
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| Molecular Formula |
C15H12F2N6O3S
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|---|---|---|
| Molecular Weight |
394.36
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| Exact Mass |
394.065
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| CAS # |
443797-96-4
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| Related CAS # |
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| PubChem CID |
5330790
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| Appearance |
White to off-white solid powder
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| Density |
1.7±0.1 g/cm3
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| Boiling Point |
676.6±65.0 °C at 760 mmHg
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| Melting Point |
149-155ºC
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| Flash Point |
363.0±34.3 °C
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| Vapour Pressure |
0.0±2.1 mmHg at 25°C
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| Index of Refraction |
1.724
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| LogP |
0.18
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
27
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| Complexity |
630
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
KDKUVYLMPJIGKA-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C15H12F2N6O3S/c16-10-2-1-3-11(17)12(10)13(24)23-14(18)21-15(22-23)20-8-4-6-9(7-5-8)27(19,25)26/h1-7H,(H2,19,25,26)(H3,18,20,21,22)
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| Chemical Name |
4-((5-amino-1-(2,6-difluorobenzoyl)-1H-1,2,4-triazol-3-yl)amino)benzenesulfonamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.27 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (5.27 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 0.5% methylcellulose+0.2% Tween 80:14mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5358 mL | 12.6788 mL | 25.3575 mL | |
| 5 mM | 0.5072 mL | 2.5358 mL | 5.0715 mL | |
| 10 mM | 0.2536 mL | 1.2679 mL | 2.5358 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
ABL2 bound to a type I inhibitor2. (A) ABL2:2, showing the compound bound to the ATP binding site, and the ordered activation loop. Compound2is shown in yellow.J Med Chem.2011 Apr 14;54(7):2359-67. |
Myristate binding pocket of ABL2. (A) Surface of the myristate binding pocket of ABL2, with imatinib shown as a yellow ball-and-stick representation.J Med Chem.2011 Apr 14;54(7):2359-67. |
Comparison of ABL2:imatinib and ABL2:1with ABL1:imatinib and ABL1:1.J Med Chem.2011 Apr 14;54(7):2359-67. |
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