AZ14289671
AZ14289671 is an orally active, blood-brain barrier-penetrant tyrosine kinase (tyrosine kinase) inhibitor (TKI) that specifically targets non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations (EGFRExon20Ins), while largely sparing wild-type EGFR to reduce off-target toxicities such as rash and diarrhea. AZ14289671 inhibits the downstream MAPK/ERK/AKT pathway, suppressing tumor cell proliferation, survival and migration. AZ14289671 can be used for NSCLC research.
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- CAS No.: 3101563-22-5
- Formule: C23H14Cl2F2N6O
- Masse moléculaire:499.30
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Stockage:
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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Activité biologique
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Chemical Information
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Activité biologique
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EGFR exon 20 insertion |
AZ14289671 (1 μM) exhibits high kinome selectivity, with only a small subset of non-EGFR family kinases showing inhibition rates exceeding 50%[1].
AZ14289671 (2 h) potently inhibits EGFR phosphorylation in EGFRExon20Ins cell lines (mean IC50 = 17-41 nM), with significantly reduced activity in EGFRWT cell lines (mean IC50 = 480-832 nM), exhibiting high mutant selectivity[1].
AZ14289671 (2 h) potently inhibits ERK phosphorylation in LXF2478ASV EGFR Exon20Ins cells, with a mean IC50 of 32 nM[1].
AZ14289671 (10-1000 nmol/L; 2 h, 6 h) potently inhibits MAPK pathway signaling (including phosphorylation of ERK, AKT and S6) in LXF2478ASV EGFRExon20Ins cells after 2 h and 6 h of treatment[1].
AZ14289671 (30-1000 nM; 6 h) dose-dependently inhibits the gene expression of the MAPK pathway in LXF2478ASV EGFR exon 20 insertion mutant cells[1].
AZ14289671 (2 h) potently inhibits EGFR phosphorylation in EGFRExon20Ins/T790M, EGFRL858R, EGFRL858R/T790M and EGFREx19del cell lines (mean IC50 = 7-45 nM), and suppresses HER2 phosphorylation in BT-474HER2WT and H2170HER2YVMA cells with mean IC50 values of 75 nM and 125 nM, respectively[1].
AZ14289671 (1 μM; 2 h) exhibits low propensity as an efflux transporter substrate, with an efflux ratio of 1.5 in MDCKII-MDR1-BCRP cells and 4.7 in MDCKI-MDR1 cells[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:LXF2478ASV EGFRExon20Ins cell line
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Concentration:10, 30, 100, 300 and 1000 nM
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Incubation Time:2 h; 6 h
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Result:Inhibited downstream EGFR signaling pathways after both 2 and 6 h of treatment, with the most robust inhibition observed for ERK phosphorylation.
Showed evident inhibition of AKT and S6 phosphorylation in a dose-dependent manner.
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Cell Line:LXF2478ASV EGFRExon20Ins cell line
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Concentration:30, 100, 300 and 1000 nM
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Incubation Time:6 h
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Result:Caused significant, dose-dependent inhibition of MAPK pathway gene expression at 30 nM and above.
Observed significant downregulation for CCND1, DUSP6, EPHA2, EPHA4, ETV5, and SPRY4, correlating with immunoblotting data showing reduced MAPK signaling.
AZ14289671 (6.25-50 mg/kg; p.o.; twice daily; for 14 consecutive days) exhibits significantly lower tumor growth inhibitory activity (maximum TGI of 62%) and EGFR phosphorylation inhibition in the H2073WT xenograft mouse model[1].
AZ14289671 (50 mg/kg; p.o.; twice daily; for 16 consecutive days) induces 86% TGI in the A431WT xenograft mouse model[1].
AZ14289671 (6.25-50 mg/kg; p.o.; twice daily; for 28 consecutive days) induces dose-dependent tumor growth inhibition in the LU3075DNP xenograft mouse model[1].
AZ14289671 (25-50 mg/kg; p.o.; twice daily; for 28 consecutive days) induces dose-dependent tumor growth inhibition in the LU0387NPH xenograft mouse model[1].
AZ14289671 (2 μmol/kg/h; intravenous injection; continuous infusion; 4 h) crosses the blood-brain barrier of healthy rats, with a Kpuu value of 0.17[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Hsd:Athymic Nude-Foxn1nu (female; subcutaneous xenograft of LXF2478ASV patient-derived EGFR exon 20 insertion mutant cells)[1]
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Dosage:6.25 mg/kg (twice daily dosing); 12.5 mg/kg (twice daily dosing; single dose); 25 mg/kg (twice daily dosing; single dose); 50 mg/kg (twice daily dosing; single dose)
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Administration:p.o.; twice daily; 14 days; p.o.; single dose
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Result:Achieved 71% TGI at 6.25 mg/kg, 81% TGI at 12.5 mg/kg, 112% TGI at 25 mg/kg, and 121% TGI after 14 days of twice daily dosing.
Significantly reduced EGFR phosphorylation at 1 and 6 hours post single dose across all dose levels, with >90% reduction observed at 6 hours post 50 mg/kg single dose.
Showed recovery of EGFR phosphorylation at 16 and 24 hours post single dose.
Maintained free plasma concentrations exceeding the IC90 for approximately 6 hours post single dose.
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Animal Model:C.B-17/lcrHanHsd-Prkdcscid (female; subcutaneous xenograft of H2073WT EGFR wild-type cells)[1]
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Dosage:6.25 mg/kg (twice daily dosing); 12.5 mg/kg (twice daily dosing; single dose); 25 mg/kg (twice daily dosing; single dose); 50 mg/kg (twice daily dosing; single dose)
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Administration:p.o.; twice daily; 14 days; p.o.; single dose
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Result:Achieved 47% TGI at 6.25 mg/kg, 53% TGI at 12.5 mg/kg, 55% TGI at 25 mg/kg, and 62% TGI after 14 days of twice daily dosing.
Induced markedly lower EGFR phosphorylation inhibition than in mutant models, with 50 mg/kg inducing ~50% inhibition at 6 hours post single dose.
Failed to reach free plasma concentrations exceeding the IC50 at any dose level post single dose.
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Animal Model:C.B-17/lcrHanHsd-Prkdcscid (female; subcutaneous xenograft of A431WT EGFR wild-type cells)[1]
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Dosage:50 mg/kg
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Administration:p.o.; twice daily; 16 days
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Result:Achieved 86% TGI after 16 days of twice daily dosing.
Was well tolerated with body weight loss < 15%.
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Animal Model:BALB/cNj-Foxn1nu/Gpt (female; subcutaneous xenograft of LU3075DNP patient-derived EGFR D770_N771InsPG exon 20 insertion mutant cells)[1]
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Dosage:6.25 mg/kg (twice daily dosing); 12.5 mg/kg (twice daily dosing; single dose); 25 mg/kg (twice daily dosing; single dose); 50 mg/kg (twice daily dosing; single dose)
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Administration:p.o.; twice daily; 28 days; p.o.; single dose
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Result:Achieved 27% TGI at 6.25 mg/kg, 81% TGI at 12.5 mg/kg, 159% TGI at 25 mg/kg, and 169% TGI after 28 days of twice daily dosing.
Significantly inhibited EGFR phosphorylation at all dose levels post single dose, with > 75% inhibition observed at 1 and 6 hours post 25 mg/kg and 50 mg/kg single doses.
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Animal Model:BALB/cNj-Foxn1nu/Gpt (female; subcutaneous xenograft of LU0387NPH patient-derived EGFR N771_H773InsH exon 20 insertion mutant cells)[1]
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Dosage:25 mg/kg; 50 mg/kg
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Administration:p.o.; twice daily; 28 days
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Result:Achieved 45% TGI at 25 mg/kg and 133% TGI at 50 mg/kg after 28 days of twice daily dosing.
Chemical Information
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CAS No. 3101563-22-5
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Masse moléculaire 499.30
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Formule C23H14Cl2F2N6O
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SMILES
O=C(N1CC2=C(C1)N(C3=CC=NC=N3)C(C4=C(F)C=C(F)C(C5=C(Cl)N=CC(Cl)=C5)=C4)=N2)C=C
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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)
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