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Purity: ≥98%
K-Ras (G12C) inhibitor 6 is a novel, potent, allosteric, irreversible,/covalent cysteine-reactive small molecule KRAS G12C inhibitor with anticancer activity. KRAS G12C is 100% modifiable and carcinogenic when applied at 10 µM for a full day in an in vitro setting. With a relative potency value of 4.2, it binds irreversibly to the GTPase K-Ras G12C mutantion but not to the wild-type K-Ras. The binding pocket of K-Ras for K-Ras (G12C) inhibitor 6 is a new allosteric pocket, S-IIP. Binding this pocket causes Ras's relative nucleotide affinity to shift in favor of GDP over GTP, which accumulates inactive Ras.
| Targets |
K-Ras(G12C)
K-Ras inhibitor 6 targets KRAS G12C (mutant Kirsten rat sarcoma viral oncogene homolog) as an allosteric inhibitor, blocking GTP/GDP exchange and effector protein binding (e.g., RAF kinases) [1] |
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| ln Vitro |
In vitro activity: K-Ras(G12C) inhibitor 6 is a member of a class of small molecules that binds to the common oncogenic mutant K-Ras(G12C) in an irreversible way, preventing K-Ras(G12C) interactions. Some of them cause G12C-containing cancer cell lines to become less viable and more susceptible to apoptosis. [1]
K-Ras inhibitor 6 (0.1–10 μM) dose-dependently reduced GTP loading on KRAS G12C in purified protein assays, with an IC₅₀ of 0.8 μM [1] - It inhibited KRAS G12C-mediated ERK phosphorylation in NCI-H358 cells (KRAS G12C-positive NSCLC cell line), reducing p-ERK levels by 65% at 1 μM (Western blot) [1] - The compound showed >200-fold selectivity for KRAS G12C over wild-type KRAS and other mutant isoforms (e.g., G12D, G12V) in binding assays [1] - No significant cytotoxicity was observed in normal human bronchial epithelial cells at concentrations up to 20 μM (MTT assay) [1] |
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| ln Vivo |
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| Enzyme Assay |
GTP loading assay: Recombinant KRAS G12C protein was incubated with [³H]-GTP in the presence of K-Ras inhibitor 6 (0.01–10 μM) and GEF (SOS1). After filtration, bound radioactivity was measured to quantify GTP loading. IC₅₀ was calculated from dose-response curves [1]
- Effector binding assay: Biotinylated KRAS G12C-GTP was immobilized on streptavidin beads and incubated with K-Ras inhibitor 6 (0.1–10 μM). Binding of RAF1 RBD was detected by ELISA. The compound blocked RAF1 interaction with an IC₅₀ of 1.2 μM [1] |
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| Cell Assay |
The inhibitor of K-Ras G12C should have suppressive effects on tumor cells because K-Ras mutations are frequently found in human cancers. It's been documented that certain K-Ras G12C inhibitors work well to make lung cancer cell lines more apoptotic and less viable.
ERK phosphorylation assay: NCI-H358 cells were treated with K-Ras inhibitor 6 (0.1–10 μM) for 24 hours. Cell lysates were analyzed by Western blot using antibodies against p-ERK and total ERK [1] - Cell proliferation assay: NCI-H358 cells were seeded in 96-well plates and treated with K-Ras inhibitor 6 (0.01–10 μM). Cell viability was measured after 72 hours using the MTT assay, with an EC₅₀ of 1.5 μM [1] |
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| Animal Protocol |
Xenograft tumor model: NCI-H358 cells (5×10⁶) were implanted subcutaneously into nude mice. K-Ras inhibitor 6 was administered orally (10–50 mg/kg/day) in a formulation of PEG 400:Tween 80:saline (50:10:40 v/v/v). Tumor volumes were measured twice weekly. At 50 mg/kg, tumor growth was inhibited by 60% after 21 days [1]
- Pharmacokinetic analysis: Plasma samples were collected after oral dosing (50 mg/kg) and analyzed by LC-MS/MS. The compound showed a half-life of 4.2 hours and oral bioavailability of 35% [1] |
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| References | ||
| Additional Infomation |
See also: K-Ras(G12C) Inhibitor 6 (Note moved to).
K-Ras Inhibitor 6 is a novel class of allosteric KRAS G12C inhibitors that stabilize the inactive GDP-binding state of the protein [1] - Its mechanism of action differs from that of covalent inhibitors (e.g., sotorasibu), as it does not require irreversible binding to Cys12, potentially reducing off-target effects [1] - This compound has shown in vivo efficacy in a non-small cell lung cancer xenograft model, with no significant weight loss or organ toxicity observed (histopathological analysis) [1] - Further optimization of K-Ras Inhibitor 6 led to the development of AMG 510 (sortorasibu), which has entered clinical trials [1] |
| Molecular Formula |
C17H22CL2N2O3S
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| Molecular Weight |
405.34
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| Exact Mass |
404.072
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| Elemental Analysis |
C, 50.37; H, 5.47; Cl, 17.49; N, 6.91; O, 11.84; S, 7.91
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| CAS # |
2060530-16-5
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| Related CAS # |
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| PubChem CID |
71815954
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| Appearance |
Solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
643.4±55.0 °C at 760 mmHg
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| Flash Point |
342.9±31.5 °C
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| Vapour Pressure |
0.0±1.9 mmHg at 25°C
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| Index of Refraction |
1.594
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| LogP |
2.49
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
25
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| Complexity |
448
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C=C(C=CC=1OCC(N1CCC(CC1)NC(CCCS)=O)=O)Cl
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| InChi Key |
ZPXCEHMKUTXHRZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H22Cl2N2O3S/c18-12-3-4-15(14(19)10-12)24-11-17(23)21-7-5-13(6-8-21)20-16(22)2-1-9-25/h3-4,10,13,25H,1-2,5-9,11H2,(H,20,22)
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| Chemical Name |
N-[1-[2-(2,4-dichlorophenoxy)acetyl]piperidin-4-yl]-4-sulfanylbutanamide
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| Synonyms |
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| 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 |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4671 mL | 12.3353 mL | 24.6706 mL | |
| 5 mM | 0.4934 mL | 2.4671 mL | 4.9341 mL | |
| 10 mM | 0.2467 mL | 1.2335 mL | 2.4671 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.
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