| Description |
KRAS G12C inhibitor 57 (Compound 50) is a potent, selective, covalent and orally active KRAS G12C inhibitor with an IC50 of 0.21 μM in KRAS G12C/SOS1 binding assay. KRAS G12C inhibitor 57 induces cancer cell apoptosis[1].
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| Related Catalog |
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| Target |
KRAS(G12C):0.21 μM (IC50, KRAS G12C/SOS1 binding assay)
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| In Vitro |
KRAS G12C inhibitor 57 (Compound 50) (0-10 μM; 3 days) 对 KRAS 和 KRAS 驱动的细胞系有选择性抑制，以及对下游信号的强烈抑制[1]。 KRAS G12C inhibitor 57 (0.1-1 μM; 24 h) 诱导 H358 细胞凋亡[1]。 KRAS G12C inhibitor 57 (0.1-1 μM; 48 h) 抑制 H358 细胞肿瘤转移[1]。 Western Blot Analysis[1] Cell Line: H358 (KRAS p. G12C) cells Concentration: 0, 0.1, 0.3, 0.5, 1 and 5 μM Incubation Time: 4 and 24 h Result: Inhibited the active KRAS-GTP and the phosphorylation of ERK and AKT (MAPK and PI3K pathway) in the dose- and time-dependent manners, and strong inhibitory effects on the phosphorylation of ERK at the concentration of 0.1 μM. Increased the cleaved PARP and caspase-7 induction (24 h). Western Blot Analysis[1] Cell Line: H1975 cell line Concentration: 5, 10, and 20 μM Incubation Time: 4 h Result: Interrupted the phosphorylation of ERK. Cell Proliferation Assay[1] Cell Line: H358 cells harboring KRAS p.G12C, MIA Paca2 cells harboring KRAS p.G12C, H1975 cells harboring KRAS p.WT and A549 cells harboring KRAS p.G12S Concentration: 0-10 μM Incubation Time: 3 days Result: Displayed favourable inhibitory activities on H358 cells and MIA Paca2 cells with the IC50 values of 0.16 μM and 0.87 μM, in sharp contrast with no obvious inhibition on cell proliferation on H1975 cells (IC50 = 7.91 μM) and A549 cells (IC50 = 29.9 μM). Apoptosis Analysis[1] Cell Line: H358 cell line Concentration: 0.1, 0.3, 0.5 and 1 μM Incubation Time: 24 h Result: Induced cellular apoptosis in dose-dependent manner. Cell Migration Assay [1] Cell Line: H358 cells Concentration: 0.1, 0.5 and 1 μM Incubation Time: 48 h Result: Significantly suppressed the migration. Cell Invasion Assay[1] Cell Line: H358 cells Concentration: 0.1, 0.5 and 1 μM Incubation Time: 48 h Result: Inhibited the cellular invasion and exhibited the dose-dependent inhibitory potency.
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| In Vivo |
KRAS G12C inhibitor 57 (Compound 50) (10 and 30 mg/kg; p.o.; daily for 20 days) 对 H358异种移植模型小鼠有抗肿瘤作用。 Pharmacokinetic data of KRAS G12C inhibitor 57 (Compound 50) in ICR mice. [1] Parameter iv (3 mg/kg) Parameter po (30 mg/kg) AUC(0−t) (h*ng/mL) 801 AUC(0−t) (h*ng/mL) 600 AUC(0−∞) (h*ng/mL) 804 AUC(0−∞) (h*ng/mL) 835 C0 (ng/mL) 1964 Cmax (ng/mL) 316 T1/2 (h) 0.930 T1/2 (h) 4.79 Vss (L/kg) 4.98 Tmax (h) 0.083 CL (mL/h/kg) 3739 F (%) 10.4 AUCo‑inf (h*mg/mL) 7060 ± 1020 (14.5%) 21800 ± 2310 (10.6%) 101000 ± 16700 (16.6%) Animal Model: BALB/c-nu/nu mice, H358 xenograft model[1] Dosage: 10 mg/kg and 30 mg/kg Administration: Oral administration, daily for 20 days Result: Significantly inhibited the tumor growth in a dose-dependent manner with remarkable tumor regression at the dose of 30 mg/kg (tumor growth inhibition, TGI = 84.0%). All dosage groups were well-tolerated with no loss of body weight and no morphological damage to viscera including the heart, spleen, and kidney. Significantly suppressed the phosphorylation of ERK and AKT in tumors of nude mice when dosing orally at 10 mg/kg and 30 mg/kg. Animal Model: ICR mice[1] Dosage: 3 mg/kg or 30 mg/kg Administration: IV or PO (Pharmacokinetic Analysis) Result: Displayed reasonable clearance and half-life by iv administration. Showed a moderate oral bioavailability (F) of 10.4%.
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| References |
[1]. Song Z, et al. Identification of novel Pyrrolo [2, 3-d] Pyrimidine-based KRAS G12C inhibitors with anticancer effects. European Journal of Medicinal Chemistry, 2022: 114907.
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