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Cat. No.: HY-186283

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GNE-0749

GNE-0749 is an orally active pan-RAF inhibitor with a K_i 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 KRAS^G12C mutation-driven cancers.

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CAS No.: 2719667-13-5
화학식: C₂₃H₂₇F₂N₅O₂
분자량:443.49

보관:

Please store the product under the recommended conditions in the Certificate of Analysis.

GNE-0749 Chemical Structure

CAS No.: 2719667-13-5

Amount: USD 0.00

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Use of MCE Products

Strong Fluorescence Signal / Multi-Disciplinary Applications / High Fluorescence Specificity

Biological Activity
- 제품 설명
- IC₅₀ & Target
- Cellular Effect
- In Vitro
- Parmacokinetics
- In Vivo
Chemical Information
순도&문서
References
Calculators
Help & FAQs
Classifications
Bioz

Biological Activity

제품 설명

IC₅₀ & Target

^[3]

CRAF

0.061 nM (Ki)

BRAF

< 0.080 nM (Ki)

All Raf Isoforms :

All p38 MAPK Isoforms :

All MEK Isoforms :

All ERK Isoforms :

Cellular Effect

Cell Line	Type	Value	Description	References
A-375	IC₅₀	112 nM Compound: 7; GNE-0749	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	[PMID: 33780623]
A549	IC₅₀	2900 nM Compound: GNE-0749	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	[PMID: 34055227]
A549	IC₅₀	2900 nM Compound: 7; GNE-0749	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	[PMID: 33780623]
A549	IC₅₀	169 nM Compound: 7; GNE-0749	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	[PMID: 33780623]

In Vitro

GNE-0749 (compound 7) inhibits CRAF and BRAF with K_i 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 K_i value of 0.061 nM; it also inhibits purified BRAF kinase with a K_i value of less than 0.080 nM^[3].
GNE-0749 exhibits strong synergistic antiproliferative activity with Cobimetinib (HY-13064) in KRAS^G12S-mutant A549 cells, and its efficacy exceeds the predictions of the additive model^[1].
GNE-0749 exhibits strong synergistic antiproliferative activity with Cobimetinib in KRAS^G12D-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.

Cell Proliferation Assay^[1]

Cell Line:

KRASG12S mutant A549 cells
Concentration:

0-16 μM
Incubation Time:

24 h (compound incubation); 30 min (EdU pulse)
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

Species	Dose	Route	CL_blood	V_dss	T_1/2	F
Mice^[1]	1 mg/kg	i.v.	27	1.4 L/kg	0.8 h	/
Mice^[1]	5 mg/kg	p.o.	/	/	/	26 %
Mice^[1]	30 mg/kg	p.o.	/	/	/	60 %

In Vivo

GNE-0749 (compound 7) (10 mg/kg; p.o.; BID; 21 days) has minimal in vivo antitumor efficacy in KRAS^G12D mutant HCT116 xenograft mice, but when combined with Cobimetinib, it produces 111% tumor growth inhibition and sustained inhibition of MAPK pathway signaling^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model:

NCR nude (female, 6-8 weeks old, 24-26 g, subcutaneous xenograft of KRASG12D mutant HCT116 cells)^[1]
Dosage:

10 mg/kg
Administration:

p.o.; BID; 21 days
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

CAS No. 2719667-13-5
분자량 443.49
화학식 C₂₃H₂₇F₂N₅O₂
SMILES

CC1=CC(F)=C(C=C1NC2=CC=C3N=CN(C(C3=C2F)=O)C)NC(NCCC(C)(C)C)=O
선적

Room temperature in continental US; may vary elsewhere.
보관

Please store the product under the recommended conditions in the Certificate of Analysis.

순도&문서

Handling Instructions (2659 KB)

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

몰농도 계산기

Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

Mass Mass

Concentration Concentration

Volume Volume

Molecular Weight Molecular Weight

농도 희석 계산기

Concentration _(start) × Volume _(start) = Concentration _(final) × Volume _(final)

Concentration _(start) Concentration _(start)

Volume _(start) Volume _(start)

Concentration _(final) Concentration _(final)

Volume _(final) Volume _(final)

Help & FAQs

How should lyophilized recombinant proteins be reconstituted and stored?

1. Before opening the cap, centrifuge the vial at 13000 rpm for 20-30 seconds. This step will ensure that any lyophilized powder that may have adhered to the cap or walls is collected at the bottom of the vial, minimizing the risk of product loss.

Bioz

MOQ

Minimum order quantity

100 mg

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Amount: USD 0.00

Biological Activity
- 제품 설명
- IC₅₀ & Target
- In Vitro
- In Vivo
Chemical Information
순도&문서
References

상품명:
Cat. No.:
수량:
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상품명:
CAS No.:
Species:
Purity:
수량:

GNE-0749

All Raf Isoforms

All p38 MAPK Isoforms

All MEK Isoforms

All ERK Isoforms