Kobe0065

Ras inhibitor CAS# 436133-68-5

Kobe0065

Catalog No. BCC5290----Order now to get a substantial discount!

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Chemical structure

Kobe0065

3D structure

Chemical Properties of Kobe0065

Cas No. 436133-68-5 SDF Download SDF
PubChem ID 3827663 Appearance Powder
Formula C15H11ClF3N5O4S M.Wt 449.79
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 42.5 mg/mL (94.49 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 1-(3-chloro-4-methylphenyl)-3-[2,6-dinitro-4-(trifluoromethyl)anilino]thiourea
SMILES CC1=C(C=C(C=C1)NC(=S)NNC2=C(C=C(C=C2[N+](=O)[O-])C(F)(F)F)[N+](=O)[O-])Cl
Standard InChIKey KSJVAYBCXSURMQ-UHFFFAOYSA-N
Standard InChI InChI=1S/C15H11ClF3N5O4S/c1-7-2-3-9(6-10(7)16)20-14(29)22-21-13-11(23(25)26)4-8(15(17,18)19)5-12(13)24(27)28/h2-6,21H,1H3,(H2,20,22,29)
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 Kobe0065

DescriptionH-Ras-cRaf1 interaction inhibitor; inhibits Raf signaling. Selectively attenuates proliferation and induces apoptosis of cancer cells harboring Ras oncogenes. Reduces growth of K-Ras mutant SW480 colon carcinoma cell xenografts in mice. Orally active.

Kobe0065 Dilution Calculator

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Preparing Stock Solutions of Kobe0065

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.2233 mL 11.1163 mL 22.2326 mL 44.4652 mL 55.5815 mL
5 mM 0.4447 mL 2.2233 mL 4.4465 mL 8.893 mL 11.1163 mL
10 mM 0.2223 mL 1.1116 mL 2.2233 mL 4.4465 mL 5.5581 mL
50 mM 0.0445 mL 0.2223 mL 0.4447 mL 0.8893 mL 1.1116 mL
100 mM 0.0222 mL 0.1112 mL 0.2223 mL 0.4447 mL 0.5558 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 Kobe0065

Kobe0065 is a small-molecule inhibitor of Ras with Ki value of 46 μM for the binding of H-Ras.GTP to c-Raf-1 [1].

Kobe0065 is a compound screened out by an in silico screen method as a potent inhibitor of the Ras–Raf interaction. It showed favorite efficacy to inhibit the binding of M-Ras.GTP and H-Ras.GTP to the Ras-binding domain of c-Raf-1. Kobe0065 also dose-dependently inhibited the binding of H-RasG12V to c-Raf-1 in NIH 3T3 cells with a rough IC50 value of 10 μM. Besides that, 20 μM of Kobe0065 effectively suppressed the phosphorylation of down-stream kinases of Raf, including MEK and ERK. In NIH 3T3 cells transfected with H-rasG12V, Kobe0065 inhibited the colony formation with IC50 value of 0.5 μM. Kobe0065 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 Kobe0065 resulted in 40-50% inhibition of the tumor growth at dose of 80 mg/kg. This effect turned to be more distinct when the dose was up to 160 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 Kobe0065

Ras inhibitors display an anti-metastatic effect by downregulation of lysyl oxidase through inhibition of the Ras-PI3K-Akt-HIF-1alpha pathway.[Pubmed:28951129]

Cancer Lett. 2017 Dec 1;410:82-91.

Metastasis stands as the major obstacle for the survival from cancers. Nonetheless most existing anti-cancer drugs inhibit only cell proliferation, and discovery of agents having both anti-proliferative and anti-metastatic properties would be more beneficial. We previously reported the discovery of small-molecule Ras inhibitors, represented by Kobe0065, that displayed anti-proliferative activity on xenografts of human colorectal cancer (CRC) cell line SW480 carrying the K-ras(G12V)gene. Here we show that treatment of cancer cells carrying the activated ras genes with Kobe0065 or a siRNA targeting Ras downregulates the expression of lysyl oxidase (LOX), which has been implicated in metastasis. LOX expression is enhanced by co-expression of Ras(G12V) through activation of phosphatidylinositol 3-kinase (PI3K)/Akt and concomitant accumulation of hypoxia-inducible factor (HIF)-1alpha. Furthermore, Kobe0065 effectively inhibits not only migration and invasion of cancer cells carrying the activated ras genes but also lung metastasis of human CRC cell line SW620 carrying the K-ras(G12V) gene. Collectively, these results indicate that Kobe0065 prevents metastasis through inhibition of the Ras-PI3K-Akt-HIF-1alpha-LOX signaling and suggest that Ras inhibitors in general might exhibit both anti-proliferative and anti-metastatic properties toward cancer cells carrying the activated ras genes.

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

Kobe0065 is a novel and effective inhibitor of Ras-Raf interaction, competitively inhibiting the binding of H-Ras·GTP to c-Raf-1 RBD with a Ki value of 46±13 μM.

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