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Purity: ≥98%
JNJ-38877605 (JNJ38877605) is an orally bioavailable small-molecule inhibitor of c-Met with potential antitumor activity. It exhibits 600-fold selectivity for inhibiting c-Met over 200 other kinases and inhibits it with an IC50 of 4 nM.
| Targets |
c-Met (IC50 = 4 nM)
MET (hepatocyte growth factor receptor). |
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| ln Vitro |
JNJ-38877605 potently inhibits HGF-stimulated and constitutively activated c-Met phosphorylation in vitro and exhibits more than 600-fold selectivity for c-Met when compared to more than 200 other diverse tyrosine and serine-threonine kinases.[1] One important factor in invasive growth that is significantly reduced in EBC1, GTL16, NCI-H1993, and MKN45 cells is JNJ-38877605 (500 nM) phosphorylation of Met and RON.[2] uPAR, IL-6, GROa, and IL-8 secretion in GTL16 cells are all modulated by JNJ-38877605, according to a recent study.
No detailed in vitro data for JNJ-38877605 are presented in the references. In reference [3], in vitro experiments demonstrated that JNJ-38877605 is as efficient as PHA665752 in modulating the secretion of IL-8, GROα, uPAR, and IL-6 in GTL16 cells (as shown in Supporting Information Fig. 3, no numerical data provided). [3] |
| ln Vivo |
JNJ-38877605, when administered orally at 40 mg/kg/day for 72 hours in mice with established GTL16 xenografts, causes a statistically significant reduction in human IL-8 plasma levels (from 0.150 ng/mL to 0.050 ng/mL) and GROα plasma levels (from 0.080 ng/mL to 0.030 ng/mL). At the same dosage, however, blood levels of uPAR drop to levels greater than 50%.[3]
In vivo activity of JNJ-38877605 was evaluated in combination with radiotherapy. In U251 glioma xenografts (CD1-nu/- mice), a single dose of 5 Gy irradiation combined with daily oral administration of JNJ-38877605 (50 mg/kg) from day -1 to day 13 significantly reduced tumor growth compared to irradiation alone (at day 13, relative tumor volume increase: vehicle = 438%, 5 Gy IR = 151%, 5 Gy IR + JNJ-38877605 = 76%; difference IR vs combination = 75%, 95% CI = 59% to 91%, P = .01). [2] In MDA-MB-231 breast cancer xenografts (NOD/SCID mice), fractionated irradiation (4.5 Gy total, 1.5 Gy on days 0,2,4) combined with daily oral JNJ-38877605 (50 mg/kg) from day 0 to 7 resulted in tumor regression (at day 7, relative volume increase: vehicle = 169%, JNJ-38877605 alone = 136%, IR alone = 131%, combination = 34%; difference IR vs combination = 97%, 95% CI = 80% to 114%, P = .006). [2] In GTL16 gastric carcinoma xenografts, oral administration of JNJ-38877605 (40 mg/kg/day for 3 days) led to a significant decrease in plasma levels of human IL-8 (from ~0.150 to 0.050 ng/ml) and GROα (from 0.080 to 0.030 ng/ml), a >50% reduction in uPAR (not statistically significant due to variability), and an increase in IL-6 from underthreshold to ~0.015 ng/ml. [3] |
| Enzyme Assay |
JNJ-38877605 is an ATP-competitive inhibitor of c-Met with an IC50 of 4 nM that is 600 times more selective for c-Met than 200 other tyrosine and serine-threonine substrates.
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| Cell Assay |
No detailed cell assay protocols for JNJ-38877605 are described.
Reference [3] mentions that in vitro experiments (Supporting Information Fig. 3) showed JNJ-38877605 modulates secretion of IL-8, GROα, uPAR, and IL-6 in GTL16 cells similarly to PHA665752, but no protocol or numerical data are given. [3] |
| Animal Protocol |
GTL16 cells are inoculated subcutaneously into the right posterior flank (or both right and left posterior flanks, for determination of uPAR and IL-6) of 6-week-old immunodeficient nu/nu female mice on Swiss CD1 background.
≤40 mg/kg/day Administered via p.o. For U251 xenografts: JNJ-38877605 was administered daily by oral gavage at 50 mg/kg, starting one day before irradiation (day -1) and continuing until day 13. A single dose of 5 Gy total body irradiation was given on day 0. [2] For MDA-MB-231 xenografts: JNJ-38877605 was administered daily by oral gavage at 50 mg/kg from day 0 to day 7. Fractionated irradiation (4.5 Gy total) was given as 1.5 Gy doses on days 0, 2, and 4. [2] For GTL16 xenografts: JNJ-38877605 was dosed orally at 40 mg/kg once daily for 3 days. Blood was sampled from tail vein at 0 and 72 hours, or from heart at sacrifice. [3] |
| ADME/Pharmacokinetics |
JNJ-38877605 is orally bioavailable (no specific parameters such as half-life or bioavailability percentage are provided). [3]
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| Toxicity/Toxicokinetics |
JNJ-38877605 was chosen over PHA665752 for in vivo studies because PHA665752 caused tissue damage at the injection site in approximately 50% of mice (unpublished observation), whereas JNJ-38877605 can be administered orally and is endowed with a safer in vivo toxicity profile. [2][3]
No specific toxicity data (e.g., LD50, organ toxicity) are provided. |
| References | |
| Additional Infomation |
6-[difluoro-[6-(1-methyl-4-pyrazolyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl]quinoline belongs to the quinoline class of compounds. JNJ-38877605 has been used in clinical trials for tumor treatment research. The c-Met inhibitor JNJ-38877605 is a small molecule receptor tyrosine kinase inhibitor with high oral bioavailability and potential anti-tumor activity. JNJ-38877605 selectively inhibits c-Met, a receptor tyrosine kinase (RTK) involved in cancer cell survival, invasion, and tumor angiogenesis. c-Met is also known as the hepatocyte growth factor receptor (HGFR).
JNJ-38877605 is a MET kinase inhibitor developed by Janssen Research & Development. It is a small-molecule inhibitor that displays selectivity and inhibitory activity against MET comparable to or higher than PHA665752. [2] It was used in preclinical combination studies with radiotherapy to radiosensitize cancer cells and prevent radiation-induced invasiveness. [2] It was also used in gastric cancer xenograft models to identify surrogate soluble biomarkers (IL-8, GROα, uPAR, IL-6) of response to MET inhibition. [3] |
| Molecular Formula |
C19H13F2N7
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| Molecular Weight |
377.35
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| Exact Mass |
377.12
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| Elemental Analysis |
C, 60.48; H, 3.47; F, 10.07; N, 25.98
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| CAS # |
943540-75-8
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| Related CAS # |
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| PubChem CID |
46911863
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.5±0.1 g/cm3
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| Index of Refraction |
1.734
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| LogP |
3.13
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
28
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| Complexity |
564
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC(C1N2C(C=CC(C3=CN(C)N=C3)=N2)=NN=1)(C1C=C2C(N=CC=C2)=CC=1)F
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| InChi Key |
JRWCBEOAFGHNNU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H13F2N7/c1-27-11-13(10-23-27)16-6-7-17-24-25-18(28(17)26-16)19(20,21)14-4-5-15-12(9-14)3-2-8-22-15/h2-11H,1H3
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| Chemical Name |
6-[difluoro-[6-(1-methylpyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl]quinoline
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| Synonyms |
JNJ38877605; JNJ 38877605; JNJ-38877605
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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 (5.51 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 (5.51 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (5.51 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 30% propylene glycol, 5% Tween 80, 65% D5W: 30 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6501 mL | 13.2503 mL | 26.5006 mL | |
| 5 mM | 0.5300 mL | 2.6501 mL | 5.3001 mL | |
| 10 mM | 0.2650 mL | 1.3250 mL | 2.6501 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00651365 | Terminated | Drug: JNJ-38877605 | Neoplasms | Johnson & Johnson Pharmaceutical Research & Development, L.L.C. |
February 2008 | Phase 1 |
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