2. GPCR/G Protein MAPK/ERK Pathway
  3. Ras
  4. 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.

KRAS G12C-IN-75

KRAS G12C-IN-75 Chemical Structure

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KRAS G12C-IN-75 Related Antibodies

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Description

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[1].

IC50 & Target[1]

KRas G12C

0.53 nM (IC50)

In Vitro

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.

KRAS G12C-IN-75 Related Antibodies
Parmacokinetics
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 %
In Vivo

KRAS G12C-IN-75 (compound 15) (1-30 mg/kg; p.o.; once daily; for 21 consecutive days) induces dose-dependent antitumor activity in the NCI-H358 xenograft model[1].
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.

Animal Model: C.B-17 SCID (inbred, female)[1]
Dosage: 1 mg/kg; 3 mg/kg; 10 mg/kg; 30 mg/kg
Administration: p.o.; daily; 21 days
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.
Animal Model: nu/nu (nude, female)[1]
Dosage: 10 mg/kg; 30 mg/kg; 100 mg/kg; 200 mg/kg
Administration: p.o.; daily; 21 days
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.
Animal Model: C.B-17 SCID (inbred, female; tumors grown to 300-500 mm3)[1]
Dosage: 10 mg/kg; 30 mg/kg
Administration: p.o.; single dose
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.
Animal Model: nu/nu (nude, female; tumors grown to 300-500 mm3)[1]
Dosage: 30 mg/kg; 100 mg/kg
Administration: p.o.; single dose
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.
Molecular Weight

538.90

Formula

C25H20ClF5N4O2
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
Shipping

Room temperature in continental US; may vary elsewhere.
Storage

Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
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KRAS G12C-IN-75 Related Classifications

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Help & FAQs
  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

KRAS G12C-IN-75RasMAPK pathwayP-glycoprotein (P-gp)CD-1 miceGDP-bound statebreast cancer resistance protein (BCRP)Cys12Sprague-Dawley ratsSPRY4KRAS G12CDUSP6Inhibitorinhibitorinhibit

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