KRAS G12C-IN-74

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KRAS G12C-IN-74 is an orally active, selective KRAS^G12C inhibitor with a target IC₅₀ of 43.18 nM. KRAS G12C-IN-74 induces G0/G1 cell cycle arrest and apoptosis in KRAS^G12C-mutant cancer cells. KRAS G12C-IN-74 is applicable for the research of KRAS^G12C-mutant pancreatic cancer, colorectal cancer and lung cancer.

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KRAS G12C-IN-74 Chemical Structure

CAS No. : 3085516-79-3

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Description

IC₅₀ & Target^[1]

KRas G12C

43.18 nM (IC₅₀)

In Vitro

KRAS G12C-IN-74 (Compound 7q) (7 days) potently inhibits the proliferation of NCI-H358 3D cell spheroids, with an IC₅₀ of 0.42 nM^[1].
KRAS G12C-IN-74 (72 h) potently inhibits the proliferation of KRAS^G12C mutant cell lines, with IC₅₀ values ranging from 0.42 nM (NCI-H358, 3D) to 3.331 μM (H1373), while it shows weak activity against non-G12C KRAS mutant cell lines and wild-type cell lines^[1].
KRAS G12C-IN-74 (200-800 nM; 48 h) induces cell cycle arrest at the G0/G1 phase and triggers apoptosis in NCI-H358 cells^[1].
KRAS G12C-IN-74 (1-8 μM; 48 h) induces dose-dependent apoptosis in NCI-H1373 cells, and when combined with ML385 (HY-100523) or RBN-2397 (HY-136174), the apoptosis rates after 48 h of incubation increase significantly to 81.28% and 82.75%, respectively^[1].
Combination treatment with KRAS G12C-IN-74 (72 h) and the pan-USP inhibitor PR-619 (HY-13814) drastically reduces its IC₅₀ against intrinsically resistant NCI-H1373 cells from the micromolar to the nanomolar range^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Apoptosis Analysis^[1]

Cell Line:	NCI-H1373 (KRAS^G12C mutant, intrinsically resistant) cells
Concentration:	1 μM, 4 μM, 8 μM (alone); 8 μM + 0.2 μM ML385; 8 μM + 0.2 μM RBN-2397
Incubation Time:	48 h
Result:	Induced apoptosis in H1373 cells in a dose-dependent manner, with an apoptotic rate of 34% at 8 μM. Increased the apoptotic rate to 81.28% when combined with 0.2 μM ML385, and to 82.75% when combined with 0.2 μM RBN-2397.

Parmacokinetics

Species	Dose	Route	T_1/2	C₀	AUC_0-t	AUC_0-∞	V_d	CL	MRT_0-last	T_max	C_max	MRT	F
Rat^[1]	3 mg/kg	i.v.	4.14 h	3319 ng/mL	1286 ng·h/mL	1301 ng·h/mL	13867 mL/kg	2342 mL/h/kg	3.88 h	/	/	/	/
Rat^[1]	30 mg/kg	p.o.	3.14 h	/	3112 ng·h/mL	3137 μg·h/mL	/	/	/	3.33 h	359 ng/mL	6.51 h	24.1 %

In Vivo

KRAS G12C-IN-74 (Compound 7q) (3-30 mg/kg; p.o.; once daily for 21 consecutive days) exhibits potent dose-dependent antitumor activity in the MIA PaCa-02 pancreatic cancer xenograft model^[1].
KRAS G12C-IN-74 (100 mg/kg; p.o.; once daily for 21 consecutive days) exhibits potent anti-tumor activity by inhibiting tumor growth in the SW837 colorectal cancer xenograft model^[1].
KRAS G12C-IN-74 (30-100 mg/kg; p.o.; once daily for 9-18 consecutive days) exhibits statistically significant but modest single-agent activity in the H1373 lung cancer xenograft model, and shows synergistic anti-tumor activity when combined with ML385, RBN-2397 and PR-619^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model:	NU/NU nude mice (~6 weeks old, 20-25 g)^[1]
Dosage:	3 mg/kg; 10 mg/kg; 30 mg/kg
Administration:	p.o.; daily; 21 days
Result:	Demonstrated a tumor growth inhibition (TGI) rate of 94.2% at 10 mg/kg. Achieved complete tumor responses in 2 out of 5 mice at 30 mg/kg. Maintained stable body weights across all treatment groups throughout the 21-day study.

Animal Model:	NU/NU nude mice (~6 weeks old, 20-25 g)^[1]
Dosage:	100 mg/kg
Administration:	p.o.; daily; 21 days
Result:	Achieved a tumor growth inhibition (TGI) rate of 87.2%.

Animal Model:	NU/NU nude mice (~6 weeks old, 20-25 g)^[1]
Dosage:	30 mg/kg; 100 mg/kg
Administration:	p.o.; daily; 18 days
Result:	Demonstrated statistically significant tumor growth inhibition at 100 mg/kg, with modest overall therapeutic efficacy compared to activity in other models.

Animal Model:	NU/NU nude mice (~6 weeks old, 20-25 g)^[1]
Dosage:	100 mg/kg (in combination with 25 mg/kg ML385)
Administration:	p.o.; daily; 9 days (KRAS G12C-IN-74); i.p.; daily; 9 days (ML385)
Result:	Produced substantially enhanced antitumor efficacy when combined with 25 mg/kg ML385, with significantly greater tumor growth inhibition than either monotherapy.

Animal Model:	NU/NU nude mice (~6 weeks old, 20-25 g)^[1]
Dosage:	30 mg/kg (in combination with 10 mg/kg RBN-2397)
Administration:	p.o.; daily; 15 days
Result:	Displayed marked synergistic tumor growth inhibition when combined with 10 mg/kg RBN-2397, overcoming H1373 resistance to single-agent KRAS G12C inhibition.

Animal Model:	NU/NU nude mice (~6 weeks old, 20-25 g)^[1]
Dosage:	30 mg/kg (in combination with 5 mg/kg PR-619); 100 mg/kg (in combination with 5 mg/kg PR-619)
Administration:	p.o.; daily; 15 days (KRAS G12C-IN-74); i.p.; every other day; 7 days (PR-619)
Result:	Achieved a tumor growth inhibition (TGI) rate of 50.6% when 30 mg/kg was combined with 5 mg/kg PR-619. Achieved a TGI rate of 66.3% when 100 mg/kg was combined with 5 mg/kg PR-619, with 1 out of 4 mice showing complete tumor remission. Did not show statistically significant activity versus control as a single agent at 30 mg/kg.

Molecular Weight

615.76

Formula

C₃₃H₃₈FN₇O₂S

CAS No.

3085516-79-3

SMILES

O=C(N1[C@H](CN(C2=NC(OCC34N(CCC4)CCC3)=NC5=C2CCN(C5)C6=CC=CC7=C6C(C)=CS7)CC1)CC#N)C(F)=C

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

Handling Instructions (2659 KB)

References

[1]. Tian L, et al. Design and Synthesis of KRAS^G12C Inhibitors for Antitumor Evaluation Harboring Combination Therapy with Nrf2, PARP-7, and Pan-USP Inhibitors to Alleviate Drug Resistance Synergistically. J Med Chem. 2026;69(4):4037-4058. [Content Brief]

KRAS G12C-IN-74 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-743085516-79-3RasApoptosiscolorectal cancer xenograft modelslung cancer xenograft modelsKRAS G12CapoptosisGDP-bound conformationCys12G0/G1 cell cycle arrestpancreatic cancer xenograft modelsKRAS G12C-mutant cancer cellsNCI-H358Inhibitorinhibitorinhibit

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