Kobe-2602
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MedKoo CAT#: 406580

CAS#: 454453-49-7

Description: Kobe2602, is analog of Kobe0065 , is is a potent and selective RAS inhibitor, which exhibit inhibitory activity toward H-Ras GTP-c-Raf-1 binding both in vivo and in vitro. Kobe2602 effectively inhibits 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, Kobe2602 exhibits antitumor activity on a xenograft of human colon carcinoma SW480 cells carrying the K-ras(G12V) gene by oral administration. Kobe2602 may serve as a scaffold for the development of Ras inhibitors with higher potency and specificity.


Chemical Structure

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Kobe-2602
CAS# 454453-49-7

Theoretical Analysis

MedKoo Cat#: 406580
Name: Kobe-2602
CAS#: 454453-49-7
Chemical Formula: C14H9F4N5O4S
Exact Mass: 419.03114
Molecular Weight: 419.31
Elemental Analysis: C, 40.10; H, 2.16; F, 18.12; N, 16.70; O, 15.26; S, 7.65

Price and Availability

Size Price Availability Quantity
10.0mg USD 150.0 Same day
25.0mg USD 250.0 Same day
50.0mg USD 450.0 Same day
100.0mg USD 650.0 Same day
200.0mg USD 1150.0 Same day
500.0mg USD 1950.0 Same day
1.0g USD 2850.0 2 Weeks
2.0g USD 4650.0 2 Weeks
5.0g USD 7450.0 2 Weeks
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Synonym: Kobe2602; Kobe 2602; Kobe-2602.

IUPAC/Chemical Name: 2-(2,6-dinitro-4-(trifluoromethyl)phenyl)-N-(4-fluorophenyl)hydrazinecarbothioamide

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)

SMILES Code: FC(C1=CC([N+]([O-])=O)=C(NNC(NC2=CC=C(F)C=C2)=S)C([N+]([O-])=O)=C1)(F)F

Appearance: Light yellow solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Kobe2602 is a Ras-Raf interaction inhibitor that inhibits the binding of H-Ras·GTP to c-Raf-1 RBD with a Ki of 149 μM.
In vitro activity: The effect of the compounds on the cellular activity of Raf, which is dependent on its interaction with Ras⋅GTP. 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-RasG12V. The effect of Kobe0065 and Kobe2602 was next tested on anchorage-independent proliferation of H-rasG12V–transformed NIH 3T3 cells. The compounds efficiently inhibited colony formation in soft agar in a dose-dependent manner (Fig. 3A and Fig. S3A). The IC50 values were around 0.5 and 1.4 μM for Kobe0065 (Fig. 3B) and Kobe2602 (Fig. S3B), respectively, which were comparable to the value of 2.1 μM observed for sorafenib (Fig. S3B). By contrast, the compounds failed to inhibit colony formation of NIH 3T3 cells transformed by the activated c-raf-1 gene carrying the S259A/Y340D/Y341D mutations (Fig. 3C and Fig. S4A.). Reference: Proc Natl Acad Sci U S A. 2013 May 14; 110(20): 8182–8187. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657810/
In vivo activity: The antitumor activity of the Kobe2602 was assessed by using a xenograft of SW480 cells in nude mice. Daily oral administration of the compound at the dose of 80 mg/kg caused ∼40–50% inhibition of the tumor growth. During these compound treatments the mice did not exhibit any significant body weight loss (Fig. S5). Immunostaining of the tumor sections showed that the ERK activation was substantially compromised by the compound administration (Fig. 4B). Moreover, the compound-treated tumors showed a prominent increase of apoptotic cells (Fig. S6A), suggesting a contribution of the oncogene addiction mechanism to the antitumor effect. Reference: Proc Natl Acad Sci U S A. 2013 May 14; 110(20): 8182–8187. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657810/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 39.0 93.01
Ethanol 23.0 54.85

Preparing Stock Solutions

The following data is based on the product molecular weight 419.31 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Shima F, Yoshikawa Y, Ye M, Araki M, Matsumoto S, Liao J, Hu L, Sugimoto T, Ijiri Y, Takeda A, Nishiyama Y, Sato C, Muraoka S, Tamura A, Osoda T, Tsuda K, Miyakawa T, Fukunishi H, Shimada J, Kumasaka T, Yamamoto M, Kataoka T. In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction. Proc Natl Acad Sci U S A. 2013 May 14;110(20):8182-7. doi: 10.1073/pnas.1217730110. Epub 2013 Apr 29. PMID: 23630290; PMCID: PMC3657810.
In vitro protocol: 1. Shima F, Yoshikawa Y, Ye M, Araki M, Matsumoto S, Liao J, Hu L, Sugimoto T, Ijiri Y, Takeda A, Nishiyama Y, Sato C, Muraoka S, Tamura A, Osoda T, Tsuda K, Miyakawa T, Fukunishi H, Shimada J, Kumasaka T, Yamamoto M, Kataoka T. In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction. Proc Natl Acad Sci U S A. 2013 May 14;110(20):8182-7. doi: 10.1073/pnas.1217730110. Epub 2013 Apr 29. PMID: 23630290; PMCID: PMC3657810.
In vivo protocol: 1. Shima F, Yoshikawa Y, Ye M, Araki M, Matsumoto S, Liao J, Hu L, Sugimoto T, Ijiri Y, Takeda A, Nishiyama Y, Sato C, Muraoka S, Tamura A, Osoda T, Tsuda K, Miyakawa T, Fukunishi H, Shimada J, Kumasaka T, Yamamoto M, Kataoka T. In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction. Proc Natl Acad Sci U S A. 2013 May 14;110(20):8182-7. doi: 10.1073/pnas.1217730110. Epub 2013 Apr 29. PMID: 23630290; PMCID: PMC3657810.

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1: Shima F, Yoshikawa Y, Ye M, Araki M, Matsumoto S, Liao J, Hu L, Sugimoto T, Ijiri Y, Takeda A, Nishiyama Y, Sato C, Muraoka S, Tamura A, Osoda T, Tsuda K, Miyakawa T, Fukunishi H, Shimada J, Kumasaka T, Yamamoto M, Kataoka T. In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction. Proc Natl Acad Sci U S A. 2013 May 14;110(20):8182-7. doi: 10.1073/pnas.1217730110. Epub 2013 Apr 29. PubMed PMID: 23630290; PubMed Central PMCID: PMC3657810.

2: Shima F, Yoshikawa Y, Matsumoto S, Kataoka T. Discovery of small-molecule Ras inhibitors that display antitumor activity by interfering with Ras·GTP-effector interaction. Enzymes. 2013;34 Pt. B:1-23. doi: 10.1016/B978-0-12-420146-0.00001-9. Epub 2013 Nov 7. Review. PubMed PMID: 25034098.

 



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