GNE-2181
GNE-2181 is an orally active, blood-brain barrier-penetrant pan-TEAD transcription factor inhibitor, with IC50 values of 13, 26, 61 and 17 nM against TEAD1, TEAD2, TEAD3 and TEAD4, respectively. GNE-8021 allosterically disrupts the TEAD-YAP/TAZ interaction and inhibits TEAD-mediated oncogenic transcriptional programs via the Hippo signaling pathway. GNE-8021 suppresses YAP-driven tumor cell growth. GNE-2181 inhibits the growth of intracranial tumor models in vivo. GNE-2181 can be used for research on brain metastasis of lung cancer.
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- CAS No.: 2933893-78-6
- Formule: C20H16F4N4O3
- Masse moléculaire:436.36
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
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TEAD1 13 nM (IC50) |
TEAD2 26 nM (IC50) |
TEAD3 61 nM (IC50) |
TEAD4 17 nM (IC50) |
GNE-8021 (overnight) potently inhibits the binding of YAP to purified TEAD1, TEAD2, TEAD3, and TEAD4 proteins, with IC50 values of 2, 4, 8, and 6 nM, respectively[1].
GNE-2181 (6 days) potently inhibits the proliferation of Hippo pathway-dependent NCI-H226 and MSTO-211H mesothelioma cells, with EC50 values of 3 nM and 7 nM, respectively, while it exhibits only extremely low activity against Hippo pathway-independent VMRC-LCD cells[1].
GNE-2181 (7-14 days) potently and dose-dependently inhibits colony formation of Hippo pathway-dependent NCI-H226 mesothelioma cells in soft agar, while exerting no significant effect on Hippo pathway-independent ES-2 cells[1].
GNE-2181 (48 h) downregulates YAP/TAZ-dependent proliferation-related and MAPK-related gene programs in Hippo pathway-dependent NCI-H226 mesothelioma cells, but exerts no effect on Hippo pathway-independent ES-2 cells[1].
GNE-2181 (6 days) combined with various MAPK pathway inhibitors yields synergistic benefits across multiple cancer cell lines, and particularly exhibits strong synergy with KRASG12C inhibitors in KRASG12C-mutant NCI-H2122 cells[1].
GNE-2181 (1 μM; 48 h) induces G0/G1 cell cycle arrest in Hippo pathway-dependent NCI-H226 and MSTO-211H mesothelioma cells following treatment at 1 μM for 48 h[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 cells
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Concentration:1 μM (GNE-2181); 10 μM (EdU)
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Incubation Time:48 h (GNE-2181); 20 min (EdU)
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Result:Induced a G0/G1 cell cycle arrest in both NCI-H226 and MSTO-211H cells, as shown by increased EdU-negative (G1) cells and decreased EdU-positive (S-phase) cells.
GNE-2181 (10-50 mg/kg; p.o.; daily; 21 days) demonstrates brain penetrance and significant efficacy against intracranial lung cancer brain metastases in nude mice, with daily oral doses of 10 mg/kg and 50 mg/kg reducing tumor growth and suppressing YAP/TAZ-dependent proliferation[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 mice[1]
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Dosage:10, 20 and 50 mg/kg
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Administration:p.o.; daily; 4 days or 20 days
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Result:Induced a dose- and exposure-dependent decrease in YAP/TAZ target gene signatures (with maximum inhibition at 50 mg/kg) and proliferation gene signatures, comparable in magnitude to GNE-8025 at 10 mg/kg twice daily.
Showed significant reductions in Ki67 and phospho-histone H3 (pHH3) staining in tumors from mice treated with 20 mg/kg daily, indicating decreased proliferation.
Caused significant tumor growth inhibition starting at 10 mg/kg daily in the 21-day efficacy study, with minimal impact on mouse body weight.
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Animal Model:Nude mice (6-week-old)[1]
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Dosage:10 mg/kg; 50 mg/kg
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Administration:p.o.; daily; 21 days
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Result:Showed significant reduction in intracranial tumor growth at week 3 post-treatment initiation (adjusted p=0.0049 for 10 mg/kg; adjusted p=0.0047 for 50 mg/kg).
Caused significant decreases in YAP/TAZ target gene expression and reduced Ki67 staining in tumor sections from mice treated with 50 mg/kg daily, indicating suppressed proliferation.
Was well-tolerated, with minimal impact on mouse body weight.
Chemical Information
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CAS No. 2933893-78-6
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Masse moléculaire 436.36
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Formule C20H16F4N4O3
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SMILES
C=C(C(N1CC(C1)C2=NN(C3=C2C(CO)=CC=N3)C4=CC=C(C=C4)OC(F)(F)F)=O)F
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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-2181 Related Classifications
HY-187181 Related Classifications
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