KRAS G12C-IN-75
KRAS G12C-IN-75 is an orally active, blood-brain barrier penetrant KRASG12C inhibitor with an IC50 of 0.53 nM. KRAS G12C-IN-75 attenuates active transport mediated by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). KRAS G12C-IN-75 inhibits tumor growth, regulates the expression of downstream MAPK target genes DUSP6 and SPRY4, and exhibits dose-dependent KRASG12C alkylation in KRASG12C-positive xenograft models. KRAS G12C-IN-75 can be used for research related to non-small cell lung cancer.
For research use only. We do not sell to patients.
- Formula: C25H20ClF5N4O2
- Molecular Weight:538.90
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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
Biological Activity
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KRas G12C 0.53 nM (IC50) |
KRAS G12C-IN-75 (compound 15) (18 h) inhibits the alkylation of KRASG12C in HCC1171 cells, with an IC50 of 17 nM[1].
KRAS G12C-IN-75 (1 μM; 180 min) shows an MDR1 efflux ratio of 4 and a BCRP efflux ratio of 3 in engineered gMDCK cells[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
| Species | Dose | Route | CLplasma | Vdss | T1/2 | AUC0-∞ | Bioavailability |
|---|---|---|---|---|---|---|---|
| Mice[1] | 2 mg/kg | i.v. | 7 mL/min/kg | 0.97 L/kg | 1.9 h | / | / |
| Mice[1] | 6 mg/kg | p.o. | / | / | / | 5.2 nM·h | 20 % |
| Mice[1] | 2 mg/kg | i.v. | 22 mL/min/kg | 2.5 L/kg | 2.5 h | / | / |
| Mice[1] | 6 mg/kg | p.o. | / | / | / | 3.6 μM·h | 43 % |
| Mice[1] | 1 mg/kg | i.v. | 17 mL/min/kg | 5.4 L/kg | 6.3 h | / | / |
| Mice[1] | 2 mg/kg | p.o. | / | / | / | 3.1 μM·h | 83 % |
KRAS G12C-IN-75 (10-200 mg/kg; p.o.; once daily; for 21 consecutive days) induces dose-dependent antitumor activity in the NCI-H2122 xenograft model[1].
KRAS G12C-IN-75 (10-30 mg/kg; p.o.; single administration) binds to KRASG12C and inhibits MAPK pathway signaling in a dose-dependent manner in NCI-H358 xenograft tumors, with maximal activity achieved 8-16 hours after a single oral administration[1].
KRAS G12C-IN-75 (30-100 mg/kg; p.o.; single administration) binds to KRASG12C in a dose-dependent manner and inhibits MAPK pathway signaling in NCI-H2122 xenograft tumors. A dose of 100 mg/kg is required to achieve >90% target alkylation at 8 hours after a single intragastric administration[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 (inbred, female)[1]
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Dosage:1 mg/kg; 3 mg/kg; 10 mg/kg; 30 mg/kg
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Administration:p.o.; daily; 21 days
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Result:Reduced tumor growth relative to vehicle control at 1 mg/kg.
Achieved tumor stasis at 3 mg/kg.
Induced deep tumor volume regressions at 10 mg/kg and 30 mg/kg.
Caused no loss of body weight in treated mice.
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Animal Model:nu/nu (nude, female)[1]
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Dosage:10 mg/kg; 30 mg/kg; 100 mg/kg; 200 mg/kg
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Administration:p.o.; daily; 21 days
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Result:Reduced tumor growth relative to vehicle control at 10 mg/kg.
Achieved tumor stasis at 30 mg/kg and 100 mg/kg.
Observed a reduction in tumor size over the 21-day study at 200 mg/kg.
Caused no loss of body weight in treated mice.
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Animal Model:C.B-17 SCID (inbred, female; tumors grown to 300-500 mm3)[1]
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Dosage:10 mg/kg; 30 mg/kg
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Administration:p.o.; single dose
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Result:Observed dose-dependent alkylation of KRAS G12C and reduction in mRNA expression of downstream MAPK target genes DUSP6 and SPRY4 at 10 mg/kg, with maximal target engagement and pathway inhibition at 8-16 hours post-dose, followed by gradual rebound over 72 hours.
Induced greater magnitude and duration of KRAS G12C alkylation (> 90% reduction in unalkylated KRAS G12C at 8 hours) and pathway inhibition at 30 mg/kg, with maximal effects at 8-16 hours post-dose.
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Animal Model:nu/nu (nude, female; tumors grown to 300-500 mm3)[1]
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Dosage:30 mg/kg; 100 mg/kg
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Administration:p.o.; single dose
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Result:Observed partial alkylation of KRAS G12C and reduction in DUSP6 and SPRY4 mRNA expression at 30 mg/kg.
Achieved > 90% alkylation of KRAS G12C at 8 hours post-dose, with corresponding robust reduction in DUSP6 and SPRY4 mRNA expression, correlating directly with target engagement at 100 mg/kg.
Chemical Information
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Molecular Weight 538.90
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Formula C25H20ClF5N4O2
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SMILES
NC1=C[C@]([C@]2=C(C=C3C4=C(C=NC3=C2F)OC[C@@H]5N4CCN(C(C=C)=O)C5)Cl)=C(C(C)=C1F)C(F)(F)F
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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
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
KRAS G12C-IN-75 Related Classifications
HY-181889 Related Classifications
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