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.
For research use only. We do not sell to patients.
- CAS No.: 2719667-13-5
- Formula: C23H27F2N5O2
- Molecular Weight:443.49
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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
- Purity & Documentation
- References
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Help & FAQs
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Biological Activity
Description
IC50 & Target
[3]|
CRAF 0.061 nM (Ki) |
BRAF < 0.080 nM (Ki) |
Cellular Effect
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| A-375 | IC50 |
112 nM
Compound: 7; GNE-0749
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Antiproliferative activity against human A-375 cells harboring BRAF mutant assessed as reduction in cell viability incubated for 24 hrs by Click-iT EdU cell proliferation imaging assay
Antiproliferative activity against human A-375 cells harboring BRAF mutant assessed as reduction in cell viability incubated for 24 hrs by Click-iT EdU cell proliferation imaging assay
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[PMID: 33780623] |
| A549 | IC50 |
2900 nM
Compound: GNE-0749
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Antiproliferative activity against human A549 cells harboring KRAS mutant assessed as reduction in cell viability
Antiproliferative activity against human A549 cells harboring KRAS mutant assessed as reduction in cell viability
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[PMID: 34055227] |
| A549 | IC50 |
2900 nM
Compound: 7; GNE-0749
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Antiproliferative activity against human A549 cells harboring KRAS mutant assessed as reduction in cell viability incubated for 24 hrs by Click-iT EdU cell proliferation imaging assay
Antiproliferative activity against human A549 cells harboring KRAS mutant assessed as reduction in cell viability incubated for 24 hrs by Click-iT EdU cell proliferation imaging assay
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[PMID: 33780623] |
| A549 | IC50 |
169 nM
Compound: 7; GNE-0749
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Synergistic antiproliferative activity against human A549 cells harboring KRAS mutant assessed as reduction in cell viability incubated for 24 hrs in presence of 100 nM cobimetinib by Click-iT EdU cell proliferation imaging assay
Synergistic antiproliferative activity against human A549 cells harboring KRAS mutant assessed as reduction in cell viability incubated for 24 hrs in presence of 100 nM cobimetinib by Click-iT EdU cell proliferation imaging assay
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[PMID: 33780623] |
In Vitro
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.
Parmacokinetics
In Vivo
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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CAS No. 2719667-13-5
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Molecular Weight 443.49
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Formula 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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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
[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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