GNE-0749
GNE-0749 is an orally active pan-RAF inhibitor with a Ki value of 0.061 nM against CRAF. GNE-0749 inhibits RAF dimer signaling via a DFG-out/αC-helix-in binding mode, prevents paradoxical activation of the MAPK pathway, and suppresses downstream MEK/ERK/RSK signal transduction. GNE-0749 can be used in studies related to KRASG12C mutation-driven cancers.
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- No. CAS: 2719667-13-5
- Fòrmula: C23H27F2N5O2
- Peso molecular:443.49
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Almacenamiento:
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Actividad biológica
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Chemical Information
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Actividad biológica
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CRAF 0.061 nM (Ki) |
BRAF < 0.080 nM (Ki) |
GNE-0749 (compound 7) inhibits CRAF and BRAF with Ki values of 0.061 nM and <0.080 nM, respectively, and exhibits high kinome selectivity, with only 1 out of 222 tested non-RAF kinases showing an inhibition rate >70% at 0.1 μM[1].
GNE-0749 potently inhibits purified CRAF kinase with a Ki value of 0.061 nM; it also inhibits purified BRAF kinase with a Ki value of less than 0.080 nM[3].
GNE-0749 exhibits strong synergistic antiproliferative activity with Cobimetinib (HY-13064) in KRASG12S-mutant A549 cells, and its efficacy exceeds the predictions of the additive model[1].
GNE-0749 exhibits strong synergistic antiproliferative activity with cobimetinib in KRASG12D-mutant HCT116 cells[1].
GNE-0749 inhibits the proliferation of KRAS-mutant A549 cancer cells with an IC50 of 2900 nM; when combined with cobimetinib, its potency is significantly enhanced, with the IC50 reduced to 169 nM[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:KRASG12S mutant A549 cells
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Concentration:0-16 μM
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Incubation Time:24 h (compound incubation); 30 min (EdU pulse)
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Result:Caused a robust leftward shift in dose-response in the presence of increasing doses of cobimetinib.
Showed strong, reproducible synergy confirmed by isobologram analysis and comparison to the Loewe additivity model, with observed doses required for 50% inhibition significantly lower than predicted by additive effects.
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:NCR nude (female, 6-8 weeks old, 24-26 g, subcutaneous xenograft of KRASG12D mutant HCT116 cells)[1]
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Dosage:10 mg/kg
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Administration:p.o.; BID; 21 days
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Result:Showed minimal antitumor activity, with tumors growing to ~1024 mm3 by day 21.
Caused an average ~10% body weight loss, which was tolerated by all animals through the end of the study.
When combined with cobimetinib, achieved 111% tumor growth inhibition (TGI), with tumors decreasing to a minimum volume of ~96 mm3 before slightly regrowing to ~128 mm3 by day 21.
When combined with cobimetinib, led to increased stabilization of pCRAF and improved, sustained reduction of downstream pERK and pRSK signaling through 8 h post-dose, compared to single-agent GNE-0749.
Chemical Information
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No. CAS 2719667-13-5
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Peso molecular 443.49
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Fòrmula C23H27F2N5O2
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SMILES
CC1=CC(F)=C(C=C1NC2=CC=C3N=CN(C(C3=C2F)=O)C)NC(NCCC(C)(C)C)=O
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
[1]. Huestis MP, et al. Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a 5-Fluoro-4-(3H)-quinazolinone Aryl Urea pan-RAF Kinase Inhibitor. J Med Chem. 2021;64(7):3940-3955. [Content Brief]
[2]. Harwood SJ, et al. Selected Approaches to Disrupting Protein-Protein Interactions within the MAPK/RAS Pathway. International journal of molecular sciences. 2023 Apr 17;24(8):7373. [Content Brief]
[3]. Huestis MP, et al. Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a Pyridopyridazinone pan-RAF Kinase Inhibitor. ACS medicinal chemistry letters. 2021 May 13;12(5):791-797. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
GNE-0749 Related Classifications
HY-186283 Related Classifications
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