RNK08954
Based on 1 Customer Validation
RNK08954 is an orally active KRASG12D inhibitor with a Kd of 0.0395 nM. RNK08954 selectively binds the inactive GDP-bound KRASG12D form, suppresses downstream KRAS-mediated signaling pathways p-ERK1/2 experssion. RNK08954 inhibits KRASG12D-mutant cell proliferation, induces G0-G1 cell cycle arrest, and inhibits tumor growth in mouse xenograft models. RNK08954 can be used for the research of non-small cell lung cancer, pancreatic ductal adenocarcinoma.
For research use only. We do not sell to patients.
- Purity : 98.08%
- CAS No.: 3032602-44-8
- Formula: C36H36F2N6O3
- Molecular Weight:638.71
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Storage:Powder -20°C, 3 years , 4°C, 2 years ; In solvent -80°C, 6 months , -20°C, 1 month
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Biological Activity
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Chemical Information
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Solvent & Solubility
- Protocols
- Purity & Documentation
- References
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Help & FAQs
Biological Activity
Description
IC50 & Target
[1]|
KRas G12D 0.0395 nM (Kd) |
ERK1 |
ERK2 |
In Vitro
RNK08954 potently and selectively binds to inactive GDP-bound KRASG12D with a Kd of 39.5 pM, with significantly lower affinity for other KRAS variants and wild-type KRAS[1].
RNK08954 (5-1250 nM; 6-72 h) potently inhibits KRAS downstream signaling in KRASG12D-mutant SW1990 cells, with an IC50 of <5.14 nM for p-ERK1/2 inhibition at 6 hours, and sustained inhibition through 72 hours[1].
RNK08954 (72 h) potently inhibits viability of KRASG12D-mutant human tumor cell lines with a median IC50 of 10.8 nM, and shows high selectivity against KRAS wild-type and non-G12D KRAS-mutant cells[1].
RNK08954 induces G0-G1 cell cycle arrest and cell death in KRASG12D-mutant SW1990 cells[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:Human pancreatic adenocarcinoma SW1990 cells (KRASG12D-mutant)
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Concentration:5, 15, 46, 140, 417, 1250 nmol/L
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Incubation Time:6-72 h
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Result:Caused concentration-dependent inhibition of p-ERK1/2 levels as early as 6 hours after treatment, with this effect sustained through 72 hours.
Achieved IC50 values for p-ERK1/2 inhibition of <5.14 nM at 6 hours, 5.18 nM at 24 hours, 10.67 nmol/L at 48 hours, and 9.53 nM at 72 hours.
Showed time- and concentration-dependent inhibition of p-AKT levels.
Parmacokinetics
In Vivo
RNK08954 (10-200 mg/kg; p.o.; once daily for 5 days) dose-dependently inhibits KRAS downstream signaling (p-ERK, p-S6, DUSP6) in GP2d xenografts mice, with significantly higher drug exposure in tumor tissue compared to plasma[1].
RNK08954 (25-100 mg/kg; p.o.; once daily, twice daily; 28 days) potently inhibits tumor growth in SW1990 pancreatic cancer xenografts mice, with near-complete tumor regression observed at 100 mg/kg twice daily[1].
RNK08954 (25-100 mg/kg; p.o.; once daily, twice daily; 42 days) achieves complete tumor regression in Panc 04.03 pancreatic cancer xenografts mice at a dose of 100 mg/kg twice daily[1].
RNK08954 (50-200 mg/kg; p.o.; twice daily; 35 days) drives dose-dependent tumor growth inhibition in A427 non-small cell lung cancer xenografts mice[1].
RNK08954 (100-200 mg/kg; p.o.; once daily, twice daily; 35 dyas) potently inhibits tumor growth in multiple KRASG12D-mutant pancreatic cancer PDX mice models[1].
RNK08954 (200 mg/kg; p.o.; once daily; 28 dyas) induces significant tumor shrinkage in an orthotopic HPAF-II-luc pancreatic cancer mice models at 200 mg/kg once daily[1].
RNK08954 (100 mg/kg; p.o.; once daily) inhibits tumor growth and modulates the tumor immune microenvironment by expanding CD8+ T cells in CT-26 syngeneic mice models, with enhanced efficacy when combined with anti-PD-1[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:BALB/c nude with GP2d colorectal cancer xenografts (female, 6-8 weeks old)[1]
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Dosage:6 mg/kg; 20 mg/kg; 60 mg/kg (once daily); 3 mg/kg; 10 mg/kg; 30 mg/kg; 100 mg/kg; 200 mg/kg (twice daily)
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Administration:p.o.; 30 or 35 days
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Result:Induced 70% tumor regression at 60 mg/kg once daily.
Drove substantial tumor regression at 100 mg/kg twice daily and 200 mg/kg twice daily, with tumor volumes reaching near or below 16 mm3 by day 30.
Showed dose-dependent tumor growth inhibition.
Was well tolerated with no significant body weight changes.
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Animal Model:BALB/c nude with GP2d colorectal cancer xenografts (female, 6-8 weeks old)[1]
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Dosage:10 mg/kg; 30 mg/kg; 100 mg/kg; 200 mg/kg
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Administration:p.o.; once daily for 5 days
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Result:Showed significant, sustained inhibition of p-ERK in tumor tissue, with inhibition detectable as early as 4 hours and persisting through 24 hours across all 10, 30, 100 mg/kg doses.
Inhibited p-S6 in tumor tissue at 100 mg/kg.
Resulted in ~80% inhibition of DUSP6 mRNA expression at 24 hours post single 200 mg/kg dose.
Achieved tumor exposure 51-fold, 119-fold, and 223-fold higher than plasma exposure at 10, 30, and 100 mg/kg, respectively.
- BrdU Incorporation Assay
- Somatic Cell Culture
- CFSE Dye Dilution Proliferation Assay
- Dye-dilution cell tracking and proliferation staining
- Patient-Derived Orthotopic Xenograft (PDOX)
- CCK-8/WST-8 Cell Proliferation Assay
- Protocol for Cell Cycle
- Cell Counting-Based Growth Curve Assay
- Colony Formation (Clonogenic) Assay
- Cell Viability Determination by MTT Colorimetric Assay
- EdU Incorporation Assay (Click Chemistry-Based DNA Synthesis Measurement)
- Ki-67 Immunostaining Proliferation Assay
- PCNA Immunodetection Proliferation Assay
- Flow cytometric DNA-content cell-cycle staining
- Protocol for Cell Counting and Cell Density Analysis
- Patient-Derived Xenograft (PDX)
- Splenic/Portal-Vein Liver Metastasis Xenograft
- MTT Cell Proliferation Assay
- Subcutaneous Cell-Line-Derived Xenograft
- Orthotopic Cell-Line Xenograft
- Intraperitoneal/Peritoneal Dissemination Xenograft
Clinical Trial
| NCT Number | Sponsor | Condition | Start Date |
Phase
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|---|---|---|---|---|
| NCT01329991 | 2011-05 | PHASE1 |
Chemical Information
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CAS No. 3032602-44-8
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Appearance Solid
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Molecular Weight 638.71
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Formula C36H36F2N6O3
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Color Off-white to light yellow
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SMILES
C#CC1=C(C=CC2=CC(O)=CC(C3=NC(OC)=C4C(N5CC6CCC(N6)C5)=NC(OCC7(CC7)CN8CC9CC9C8)=NC4=C3F)=C21)F
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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Solvent & Solubility
In Vitro:
DMSO : 100 mg/mL (156.57 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
In Vivo:
Select the appropriate dissolution method based on your experimental animal and administration route.
- For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
- To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for In Vivo experiments, it is recommended to prepare freshly and use it on the same day.
- The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.
Add each solvent one by one: 10% DMSO 40% PEG300 5% Tween-80 45% Saline
Solubility: ≥ 2.5 mg/mL (3.91 mM); Clear solution
This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.
Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
Add each solvent one by one: 10% DMSO 90% (20% SBE-β-CD in Saline)
Solubility: ≥ 2.5 mg/mL (3.91 mM); Suspended solution
This protocol yields a suspended solution of ≥ 2.5 mg/mL (saturation unknown). Suspended solution can be used for oral and intraperitoneal injection.
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.
In Vivo Dissolution Calculator
Please enter the basic information of animal experiments:
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Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
Please enter your animal formula composition:
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%DMSO +
Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
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%+
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+%Tween-80 + +
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%Saline +
The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
Working solution concentration: 0.22 mg/mL
Method for preparing stock solution: mg drug dissolved in μL DMSO. Stock solution concentration: mg/mL.
1. Take μL DMSO stock solution;
2. Add μL .
μL , mix evenly;
3. Then add μL Tween 80, mix evenly;
4. Then add μL
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
Purity & Documentation
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Data Sheet (285 KB)
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SDS (252 KB)
- English - EN (252 KB)
- Français - FR (252 KB)
- Deutsch - DE (252 KB)
- Norwegian - NO (252 KB)
- Español - ES (252 KB)
- Swedish - SV (252 KB)
- Italian - IT (252 KB)
- Korean - KR (252 KB)
- Portuguese - PT (252 KB)
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Handling Instructions (2659 KB)
References
Complete Stock Solution Preparation Table
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
| Optional Solvent | Concentration Solvent Mass | 1 mg | 5 mg | 10 mg | 25 mg |
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| DMSO | 1 mM | 1.5657 mL | 7.8283 mL | 15.6566 mL | 39.1414 mL |
| 5 mM | 0.3131 mL | 1.5657 mL | 3.1313 mL | 7.8283 mL | |
| 10 mM | 0.1566 mL | 0.7828 mL | 1.5657 mL | 3.9141 mL | |
| 15 mM | 0.1044 mL | 0.5219 mL | 1.0438 mL | 2.6094 mL | |
| 20 mM | 0.0783 mL | 0.3914 mL | 0.7828 mL | 1.9571 mL | |
| 25 mM | 0.0626 mL | 0.3131 mL | 0.6263 mL | 1.5657 mL | |
| 30 mM | 0.0522 mL | 0.2609 mL | 0.5219 mL | 1.3047 mL | |
| 40 mM | 0.0391 mL | 0.1957 mL | 0.3914 mL | 0.9785 mL | |
| 50 mM | 0.0313 mL | 0.1566 mL | 0.3131 mL | 0.7828 mL | |
| 60 mM | 0.0261 mL | 0.1305 mL | 0.2609 mL | 0.6524 mL | |
| 80 mM | 0.0196 mL | 0.0979 mL | 0.1957 mL | 0.4893 mL | |
| 100 mM | 0.0157 mL | 0.0783 mL | 0.1566 mL | 0.3914 mL |
RNK08954 Related Classifications
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