kobe2602

Ras inhibitor CAS# 454453-49-7

kobe2602

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Catalog No. BCC5291----Order now to get a substantial discount!

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Chemical Properties of kobe2602

Cas No. 454453-49-7 SDF Download SDF
PubChem ID 3827738 Appearance Powder
Formula C14H9F4N5O4S M.Wt 419.31
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 14.3 mg/mL (34.10 mM; Need ultrasonic and warming)
Chemical Name 1-[2,6-dinitro-4-(trifluoromethyl)anilino]-3-(4-fluorophenyl)thiourea
SMILES C1=CC(=CC=C1NC(=S)NNC2=C(C=C(C=C2[N+](=O)[O-])C(F)(F)F)[N+](=O)[O-])F
Standard InChIKey NNPBSITXCGPXJC-UHFFFAOYSA-N
Standard InChI 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)
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 kobe2602

Descriptionkobe2602 is a novel and effective small-molecule compound inhibiting Ras–Raf interaction by SBDD; exhibits potent activity to competitively inhibit the binding of H-Ras·GTP to c-Raf-1 RBD with a Ki value of 149 ± 55 μM. IC50 value: 149 ± 55 uM (Ki) [1] Target: Ras-Raf These two compounds(Kobe0065 and Kobe2602), added to the culture medium at 2 and 20 μM, effectively reduced the amount of c-Raf-1 associated with H-Ras G12V in NIH 3T3 cells in a dose-dependent manner, indicating the inhibition of the cellular activity of Ras. A rough estimate of the IC50 value for the cellular Ras–Raf-binding inhibition was around 10 μM (Fig. 1B), which was not much different from the Ki values for the in vitro Ras–Raf-binding inhibition considering thequite low cellular concentration of Raf. A similar inhibitory effect was also observed with NIH 3T3 cells overexpressing K-Ras G12V. Both Kobe0065 and Kobe2602 at 20 μM efficiently inhibited the phosphorylation of MEK and ERK, downstream kinases of Raf in NIH 3T3 cells transiently expressing H-Ras G12V, although the effect was slightly weaker than that of 2 μM sorafenib.

References:
[1]. Shima, Fumi, et al. In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction. Proceedings of the National Academy of Sciences of the United States of America (2013), 110(20), 8182-8187,

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Preparing Stock Solutions of kobe2602

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.3849 mL 11.9244 mL 23.8487 mL 47.6974 mL 59.6218 mL
5 mM 0.477 mL 2.3849 mL 4.7697 mL 9.5395 mL 11.9244 mL
10 mM 0.2385 mL 1.1924 mL 2.3849 mL 4.7697 mL 5.9622 mL
50 mM 0.0477 mL 0.2385 mL 0.477 mL 0.9539 mL 1.1924 mL
100 mM 0.0238 mL 0.1192 mL 0.2385 mL 0.477 mL 0.5962 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 kobe2602

Kobe2602 is a small-molecule inhibitor of Ras with Ki value of 149 μM [1].

Kobe2602 is a compound screened out by a computer-assisted search of about 160,000 compounds. It dose-dependently inhibited the binding of H-RasG12V to c-Raf-1 in NIH 3T3 cells with a rough IC50 value of 10 μM. 20 μM of Kobe2602 effectively suppressed the phosphorylation of down-stream kinases of Raf, including MEK and ERK. Besides that, in NIH 3T3 cells transfected with H-rasG12V, Kobe2602 inhibited the colony formation with IC50 value of 1.4 μM. Kobe2602 also showed effect on other cancer cells carrying activated ras oncogenes, such as PANC-1(K-rasG12V), HT1080 (N-rasQ61L) and HCT116 (H-rasG13D). Moreover, in mice bearing SW480 xenografts, administration of Kobe2602 resulted in 40-50% inhibition of the tumor growth at dose of 80 mg/kg [1].

References:
[1] Shima F, Yoshikawa Y, Ye M, et al. In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras–effector interaction. Proceedings of the National Academy of Sciences, 2013, 110(20): 8182-8187.

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References on kobe2602

In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction.[Pubmed:23630290]

Proc Natl Acad Sci U S A. 2013 May 14;110(20):8182-7.

Mutational activation of the Ras oncogene products (H-Ras, K-Ras, and N-Ras) is frequently observed in human cancers, making them promising anticancer drug targets. Nonetheless, no effective strategy has been available for the development of Ras inhibitors, partly owing to the absence of well-defined surface pockets suitable for drug binding. Only recently, such pockets have been found in the crystal structures of a unique conformation of RasGTP. Here we report the successful development of small-molecule Ras inhibitors by an in silico screen targeting a pocket found in the crystal structure of M-RasGTP carrying an H-Ras-type substitution P40D. The selected compound Kobe0065 and its analog kobe2602 exhibit inhibitory activity toward H-RasGTP-c-Raf-1 binding both in vivo and in vitro. They effectively inhibit both anchorage-dependent and -independent growth and induce apoptosis of H-ras(G12V)-transformed NIH 3T3 cells, which is accompanied by down-regulation of downstream molecules such as MEK/ERK, Akt, and RalA as well as an upstream molecule, Son of sevenless. Moreover, they exhibit antitumor activity on a xenograft of human colon carcinoma SW480 cells carrying the K-ras(G12V) gene by oral administration. The NMR structure of a complex of the compound with H-RasGTP(T35S), exclusively adopting the unique conformation, confirms its insertion into one of the surface pockets and provides a molecular basis for binding inhibition toward multiple RasGTP-interacting molecules. This study proves the effectiveness of our strategy for structure-based drug design to target RasGTP, and the resulting Kobe0065-family compounds may serve as a scaffold for the development of Ras inhibitors with higher potency and specificity.

Discovery of small-molecule Ras inhibitors that display antitumor activity by interfering with Ras.GTP-effector interaction.[Pubmed:25034098]

Enzymes. 2013;34 Pt. B:1-23.

Ras proteins, particularly their active GTP-bound forms (Ras.GTP), were thought "undruggable" owing to the absence of apparent drug-accepting pockets in their crystal structures. Only recently, such pockets have been found in the crystal structures representing a novel Ras.GTP conformation. We have conducted an in silico docking screen targeting a pocket in the crystal structure of M-Ras(P40D).GTP and obtained Kobe0065, which, along with its analogue kobe2602, inhibits binding of H-Ras.GTP to c-Raf-1. They inhibit the growth of H-rasG12V-transformed NIH3T3 cells, which are accompanied by downregulation of not only MEK/ERK but also Akt, RalA, and Sos, indicating the blockade of interaction with multiple effectors. Moreover, they exhibit antitumor activity on a xenograft of human colon carcinoma carrying K-rasG12V. The nuclear magnetic resonance structure of a complex of the compound with H-Ras(T35S).GTP confirms its insertion into the surface pocket. Thus, these compounds may serve as a novel scaffold for the development of Ras inhibitors with higher potency and specificity.

Description

kobe2602 is a novel and effective small-molecule compound inhibiting Ras–Raf interaction by SBDD; exhibits potent activity to competitively inhibit the binding of H-Ras·GTP to c-Raf-1 RBD with a Ki value of 149 ± 55 μM.

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