JNJ-38877605

C-Met inhibitor,ATP-competitive CAS# 943540-75-8

JNJ-38877605

Catalog No. BCC2485----Order now to get a substantial discount!

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Chemical structure

JNJ-38877605

3D structure

Chemical Properties of JNJ-38877605

Cas No. 943540-75-8 SDF Download SDF
PubChem ID 46911863 Appearance Powder
Formula C19H13F2N7 M.Wt 377.35
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 30 mg/mL (79.50 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 6-[difluoro-[6-(1-methylpyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl]quinoline
SMILES CN1C=C(C=N1)C2=NN3C(=NN=C3C(C4=CC5=C(C=C4)N=CC=C5)(F)F)C=C2
Standard InChIKey JRWCBEOAFGHNNU-UHFFFAOYSA-N
Standard InChI 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
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of JNJ-38877605

DescriptionJNJ-38877605 is an ATP-competitive inhibitor of c-Met with an IC50 value of 4 nM.
Targetsc-Met    
IC504 nM     

JNJ-38877605 Dilution Calculator

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JNJ-38877605 Molarity Calculator

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Preparing Stock Solutions of JNJ-38877605

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.6501 mL 13.2503 mL 26.5006 mL 53.0012 mL 66.2515 mL
5 mM 0.53 mL 2.6501 mL 5.3001 mL 10.6002 mL 13.2503 mL
10 mM 0.265 mL 1.325 mL 2.6501 mL 5.3001 mL 6.6251 mL
50 mM 0.053 mL 0.265 mL 0.53 mL 1.06 mL 1.325 mL
100 mM 0.0265 mL 0.1325 mL 0.265 mL 0.53 mL 0.6625 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on JNJ-38877605

JNJ-38877605 is a small-molecule ATP-competitive inhibitor of the catalytic activity of c-Met.

Extensive evidence that c-Met signaling is involved in the progression and spread of several cancers and an enhanced understanding of its role in disease have generated considerable interest in c-Met and HGF asmajor targets in anti-cancer drug development.

In vitro: JNJ-38877605 showed ~600-fold selectivity for c-Met compared with a panel of ~250 diverse tyrosine and serine-threonine kinases and was found to potently inhibit HGF-stimulated and constitutively activated c-Met phosphorylation in vitro [1].

In vivo: JNJ-38877605 showed excellent oral bioavailability approaching 100% in all examined species. In addition, JNJ-38877605 in a single dose was observed toinhibit Met phosphorylation in tumor xenografts for up to16 h. Inhibition of Met phosphorylation was associated withdose-dependent tumor growth inhibition using a range of oral dosing regimens [2].

Clinical trial: A Safety and Dose-finding Study of JNJ-38877605 in Patients With Advanced or Refractory Solid Tumors.

Reference:
[1] PereraT, L avrijssenT, Janssens B, et al.  JNJ-38877605: a selective Met kinase inhibitor inducing
regression of Met-driven tumor models.  Presented at the 99th AACR Annual Meeting; 2008 Apr 12 -16;

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References on JNJ-38877605

Effectiveness of inhibitor rapamycin, saracatinib, linsitinib and JNJ-38877605 against human prostate cancer cells.[Pubmed:26131286]

Int J Clin Exp Med. 2015 Apr 15;8(4):6563-7. eCollection 2015.

To investigate the effect of different concentrations of inhibitors rapamycin, saracatinib, linsitinib and JNJ-38877605 on PC-3 cells with CCK-8 assay, respectively. PC-3 cells were incubated with different concentrations of rapamycin, saracatinib, linsitinib and JNJ-38877605, respectively, for 48 h at 37 degrees C, the concentrations of rapamycin were 5 nM, 10 nM, 20 nM, 50 nM, 75 nM, 100 nM; Saracatinib: 0.125 nM, 0.25 nM, 0.5 nM, 1 nM, 2.5 nM, 5 nM; Linsitinib: 2 nM, 5 nM, 10 nM, 20 nM, 40 nM, 60 nM; JNJ-38877605: 0.125 nM, 0.5 nM, 1 nM, 2.5 nM, 5 nM, 10 nM. The proliferation of PC-3 cells was examined by CCK-8. Different concentrations of inhibitor rapamycin remarkably inhibited PC-3 cell proliferation after 48 h (P<0.05), inhibitory action did not change significantly from 5 nM-100 nM; different concentrations of saracatinib, linsitinib and JNJ-38877605 did not inhibit PC-3 cell proliferation after 48 h. Rapamycin treatment at low concentration can inhibit the proliferation of PC-3 cells, while saracatinib, linsitinib and JNJ-38877605 do not inhibit PC-3 cell proliferation.

The c-Met Tyrosine Kinase Inhibitor JNJ-38877605 Causes Renal Toxicity through Species-Specific Insoluble Metabolite Formation.[Pubmed:25745036]

Clin Cancer Res. 2015 May 15;21(10):2297-2304.

PURPOSE: The receptor tyrosine kinase c-Met plays an important role in tumorigenesis and is a novel target for anticancer treatment. This phase I, first-in-human trial, explored safety, pharmacokinetics, pharmacodynamics, and initial antitumor activity of JNJ-38877605, a potent and selective c-Met inhibitor. EXPERIMENTAL DESIGN: We performed a phase I dose-escalation study according to the standard 3+3 design. RESULTS: Even at subtherapeutic doses, mild though recurrent renal toxicity was observed in virtually all patients. Renal toxicity had not been observed in preclinical studies in rats and dogs. Additional preclinical studies pointed toward the rabbit as a suitable toxicology model, as the formation of the M10 metabolite of JNJ-38877605 specifically occurred in rabbits and humans. Additional toxicology studies in rabbits clearly demonstrated that JNJ-38877605 induced species-specific renal toxicity. Histopathological evaluation in rabbits revealed renal crystal formation with degenerative and inflammatory changes. Identification of the components of these renal crystals revealed M1/3 and M5/6 metabolites. Accordingly, it was found that humans and rabbits showed significantly increased systemic exposure to these metabolites relative to other species. These main culprit insoluble metabolites were generated by aldehyde oxidase activity. Alternative dosing schedules of JNJ-3877605 and concomitant probenecid administration in rabbits failed to prevent renal toxicity at dose levels that could be pharmacologically active. CONCLUSIONS: Combined clinical and correlative preclinical studies suggest that renal toxicity of JNJ-38877605 is caused by the formation of species-specific insoluble metabolites. These observations preclude further clinical development of JNJ-38877605.

Description

JNJ-38877605 is an ATP-competitive inhibitor of c-Met with IC50 of 4 nM, 600-fold selective for c-Met than 200 other tyrosine and serine-threonine kinases.

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