GNE-8025
GNE-8025 is an orally active pan-TEAD transcription factor inhibitor, with IC50 values of 45, 38, 1035 and 24 nM against TEAD1, TEAD2, TEAD3 and TEAD4, respectively. GNE-8025 allosterically disrupts the TEAD-YAP/TAZ interaction and inhibits TEAD-mediated oncogenic transcriptional programs via the Hippo signaling pathway. GNE-8025 suppresses YAP-driven tumor cell growth. GNE-8025 enhances the activity of MAPK and KRASG12C inhibitors. GNE-8025 can be used for the research of pleural mesothelioma and KRASG12C-mutant cancers.
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- CAS No.: 2933893-27-5
- Formule: C19H17F3N4O4
- Masse moléculaire:422.36
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Activité biologique
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Chemical Information
- Pureté et documentation
- Références
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Help & FAQs
Activité biologique
GNE-8025 (overnight) potently inhibits the binding of YAP to purified TEAD1, TEAD2 and TEAD4 proteins, with IC50 values of 5, 8 and 37 nM, respectively, while it shows weak inhibitory activity against TEAD3 (IC50 = 0.326 μM)[1].
GNE-8025 (6 days) potently inhibits the proliferation of Hippo pathway-dependent mesothelioma cell lines NCI-H226 (EC50 = 7 nM) and MSTO-211H (EC50 = 22 nM), while exhibits extremely low activity against the Hippo pathway-independent cell line VMRC-LCD (EC50 = 18 μM)[1].
GNE-8025 potently inhibits the proliferation of pleura-derived cancer cell lines, and its sensitivity is highly correlated with the gene expression signatures of YAP/TAZ activation, angiogenesis, and epithelial-mesenchymal transition[1].
GNE-8025 (7-14 days) potently and dose-dependently inhibits colony formation of Hippo pathway-dependent NCI-H226 mesothelioma cells, but has no effect on Hippo pathway-independent ES-2 cells[1].
GNE-8025 (48 h) downregulates the expression of YAP/TAZ target genes and proliferation genes in Hippo pathway-dependent NCI-H226 mesothelioma cells, while exerting minimal effects on Hippo pathway-independent ES-2 cells[1].
GNE-8025 (24 h) downregulates the expression of YAP/TAZ target genes and proliferation genes, and upregulates the expression of apoptosis genes in NF2-deficient mesothelioma cell lines, but exerts no effect on SK-N-FI and VMRC-LCD cells that are independent of the Hippo pathway[1].
GNE-8025 (6 days) enhances the efficacy of RTK and RAS/MAPK pathway inhibitors in various cancer cell lines, exerts synergistic growth inhibitory effects when combined with KRASG12C, EGFR and RAF inhibitors, and reduces cell proliferation and increases cell apoptosis in combination therapy by regulating transcriptional signatures[1].
GNE-8025 (1 μM; 48 h) induces G0/G1 cell cycle arrest in Hippo pathway-dependent NCI-H226 and MSTO-211H mesothelioma cell lines[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:Hippo-dependent NCI-H226 and MSTO-211H mesothelioma cell lines
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Concentration:1 μM
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Incubation Time:48 h
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Result:Induced a G0/G1 cell cycle arrest in both NCI-H226 and MSTO-211H cells, as shown by reduced EdU-positive (S-phase) cells compared to DMSO control.
GNE-8025 (3-20 mg/kg; p.o.; once daily or twice daily; 21 days) effectively inhibits tumor growth of MSTO-211H mesothelioma xenografts in mouse models[1].
GNE-8025 (1.5-10 mg/kg; p.o.; twice daily; for 21 days) effectively inhibits tumor growth when administered twice daily for 21 days in the PXF1752 mesothelioma patient-derived xenograft mouse model[1].
GNE-8025 (10-20 mg/kg; p.o.; once daily or twice daily; for 21 consecutive days) does not inhibit tumor growth in the Hippo pathway-independent ES-2 ovarian cancer xenograft mouse model, confirming its specificity for tumors with Hippo pathway dysregulation[1].
GNE-8025 (0.5-10 mg/kg; p.o.; twice daily; 20-21 days) significantly enhances the antitumor efficacy of Divarasib in a mouse model of NCI-H2122 KRASG12C-mutant lung adenocarcinoma xenografts[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C.B-17 SCID[1]
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Dosage:0.025, 0.05, 0.1, 0.25, 0.5, 1.5, 5, 10 and 25 and 50 mg/kg
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Administration:p.o.; daily or twice daily; 4 days or 21 days
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Result:Achieved dose-proportional decrease in YAP/TAZ target score up to 20 mg/kg daily, with no further improvement at 50 mg/kg daily.
Achieved equivalent YAP/TAZ target score inhibition with 20 mg/kg daily and 10 mg/kg twice daily.
Maintained YAP/TAZ target score for 24 hours post-last dose at 3 mg/kg daily and 50 mg/kg daily, with rebound starting at 31 hours post-dose for 50 mg/kg daily.
Significantly reduced ANKRD1 and CTGF transcript levels with 10 mg/kg twice daily.
Significantly reduced Ki67 and phospho-histone H3 (pHH3) levels with 20 mg/kg daily.
Significantly inhibited tumor growth starting at 1.5 mg/kg twice daily and 10 mg/kg daily in 21-day study, with efficacy plateauing at 20 mg/kg daily or 10 mg/kg twice daily.
Achieved dose-proportional decrease in YAP/TAZ target score starting at 1.5 mg/kg twice daily in PK/PD study, with chromatin accessibility at YAP/TAZ-TEAD binding sites decreasing dose-dependently starting at 1.5 mg/kg twice daily and plateauing at 10 mg/kg twice daily.
Achieved rapid pathway inhibition (within 2 days), with rebound above EC50 threshold at 24 hours post-last dose for 1.5 mg/kg twice daily, and suppression maintained to 31 hours post-last dose for 10 mg/kg twice daily.
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Animal Model:C.B-17 SCID[1]
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Dosage:3 mg/kg; 20 mg/kg
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Administration:p.o.; daily or twice daily; 21 days
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Result:Demonstrated significant anti-tumor activity in MSTO-211H xenografts.
Caused minimal impact on mouse body weight.
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Animal Model:Immunocompromised mice[1]
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Dosage:1.5 mg/kg; 10 mg/kg
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Administration:p.o.; twice daily; 21 days
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Result:Demonstrated significant anti-tumor activity in the PXF1752 PDX model.
Caused minimal impact on mouse body weight.
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Animal Model:C.B-17 SCID[1]
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Dosage:10 mg/kg; 20 mg/kg
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Administration:p.o.; daily or twice daily; 21 days
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Result:Showed no response in ES-2 xenografts.
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Animal Model:Immunocompromised mice[1]
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Dosage:0.5, 1.5, 2.5 and 10 mg/kg (single agent or combination with Divarasib (HY-145928) 5-50 mg/kg daily)
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Administration:p.o.; twice daily; 20-21 days
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Result:Showed minimal anti-tumor activity as single agent, with tumor growth tracking vehicle control.
Dose-dependently enhanced efficacy when combined with Divarasib (25 mg/kg daily), resulting in tumor regression with TGI values ranging from 108% to 121%.
Resulted in tumor regressions across all groups when 10 mg/kg twice daily was combined with Divarasib 5-50 mg/kg daily, with maximum TGI values reaching 127%.
Dose-dependently suppressed YAP/TAZ transcriptional signatures as single agent.
Combination treatment with Divarasib resulted in more profound suppression of both YAP/TAZ and MAPK signatures compared to single agents.
Chemical Information
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CAS No. 2933893-27-5
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Masse moléculaire 422.36
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Formule C19H17F3N4O4
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SMILES
C=CC(NCC1=NN(C2=C1C([C@@H](CO)O)=CC=N2)C3=CC=C(C=C3)OC(F)(F)F)=O
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
GNE-8025 Related Classifications
HY-187180 Related Classifications
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