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Purity: ≥98%
kobe2602 is a novel, potent and selective small-molecule inhibitor of Ras–Raf interaction identified by SBDD (structure based drug design); it exhibits competitively inhibits the binding of H-Ras·GTP to c-Raf-1 RBD with a Ki value of 149 ± 55 μM. Kobe2602 is an analog of Kobe0065 that efficiently suppresses H-ras(G12V)-transformed NIH 3T3 cells' anchorage-dependent and independent growth and induces apoptosis. This is accompanied by the down-regulation of downstream molecules like MEK/ERK, Akt, and RalA as well as an upstream molecule called Son of Sevenless. Furthermore, oral administration of Kobe2602 results in antitumor activity on a xenograft of human colon carcinoma SW480 cells carrying the K-ras(G12V) gene. Kobe2602 might act as a building block for the creation of more potent and selective Ras inhibitors.
| Targets |
Ras-Raf interaction ( Ki = 149 μM )
|
|---|---|
| ln Vitro |
Kobe2602 (2–20 μM; 1 hour) shows Ras–Raf–binding inhibition in NIH 3T3 cells[1].
Kobe2602 inhibits cellular Ras-Raf binding with an IC50 value of roughly 10 μM[1]. Kobe2602 (20 μM) effectively suppresses the phosphorylation of Raf downstream kinases MEK and ERK in NIH 3T3 cells that are transiently expressing H-RasG12V[1]. Kobe2602 inhibits Ras⋅GTP but not Ras⋅GDP[1]. Kobe2602 (20 μM) prevents H-RasG12V-transformed cells from proliferating anchorage-dependently[1]. |
| ln Vivo |
Kobe2602 (80 mg/kg; p.o.; five consecutive days per week; for 17 days) demonstrates antitumor activity against a xenograft of K-RasG12V-carrying human colon carcinoma SW480 cells[1].
|
| Cell Assay |
Cell Line: H-rasG12V-transformed NIH 3T3 cells
Concentration: 20 μM Incubation Time: 24 hours , 48 hours, 72 hours Result: Efficiently inhibited colony formation in soft agar in a dose-dependent manner. |
| Animal Protocol |
Female athymic nude mice (6-8 wk old), with SW480 cells xenograft
80 mg/kg Oral administration, five consecutive days per week, for 17 days |
| References |
| Molecular Formula |
C14H9N5O4F4S
|
|---|---|
| Molecular Weight |
419.31096
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| Exact Mass |
419.03
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| Elemental Analysis |
C, 40.10; H, 2.16; F, 18.12; N, 16.70; O, 15.26; S, 7.65
|
| CAS # |
454453-49-7
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| Appearance |
Light yellow solid powder
|
| SMILES |
C1=CC(=CC=C1NC(=S)NNC2=C(C=C(C=C2[N+](=O)[O-])C(F)(F)F)[N+](=O)[O-])F
|
| InChi Key |
NNPBSITXCGPXJC-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C14H9F4N5O4S/c15-8-1-3-9(4-2-8)19-13(28)21-20-12-10(22(24)25)5-7(14(16,17)18)6-11(12)23(26)27/h1-6,20H,(H2,19,21,28)
|
| Chemical Name |
1-[2,6-dinitro-4-(trifluoromethyl)anilino]-3-(4-fluorophenyl)thiourea
|
| Synonyms |
Kobe 2602; Kobe2602; Kobe-2602
|
| 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 |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO: 14.3~84 mg/mL (34.1~200.3 mM)
Ethanol: ~14 mg/mL |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (11.92 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 50.0 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. Solubility in Formulation 2: ≥ 5 mg/mL (11.92 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 50.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3849 mL | 11.9244 mL | 23.8487 mL | |
| 5 mM | 0.4770 mL | 2.3849 mL | 4.7697 mL | |
| 10 mM | 0.2385 mL | 1.1924 mL | 2.3849 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.
 Inhibition of various downstream targets of Ras by the Kobe0065-family compounds.
Molecular basis for the interaction of Ras⋅GTP with the Kobe0065-family compounds.Proc Natl Acad Sci U S A.2013 May 14;110(20):8182-7. |
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 Inhibition of Sos by the Kobe0065-family compounds and effect of the Sos activity on the cellular RasG12V⋅GTP level.
Anti-proliferative activity of the Kobe0065-family compounds on a tumor xenograft.Proc Natl Acad Sci U S A.2013 May 14;110(20):8182-7. |
 Inhibition of proliferation of H-rasG12V–transformed cells by the Kobe0065-family compounds.Proc Natl Acad Sci U S A.2013 May 14;110(20):8182-7. |
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