RNK08954
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.
- CAS No.: 3032602-44-8
- Formula: C36H36F2N6O3
- Molecular Weight:638.71
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biological Activity
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Chemical Information
- Purity & Documentation
- References
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Help & FAQs
Biological Activity
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KRas G12D 0.0395 nM (Kd) |
ERK1 |
ERK2 |
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.
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.
| NCT Number | Sponsor | Condition | Start Date |
Phase
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|---|---|---|---|---|
| NCT01329991 | Plexxikon| | 2011-05 | PHASE1 |
Chemical Information
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CAS No. 3032602-44-8
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Molecular Weight 638.71
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Formula C36H36F2N6O3
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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
Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
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