KRAS G12C inhibitor 57 (Compound 50) 是一种有效的、选择性的、共价的和具有口服活性的KRAS G12C抑制剂，在 KRAS G12C/SOS1 结合试验中对 KRAS G12C 的IC50为 0.21 μM。KRAS G12C inhibitor 57 诱导癌细胞凋亡 (apoptosis)。
| 生物活性 | KRAS G12C inhibitor 57 (Compound 50) is a potent, selective, covalent and orally activeKRAS G12Cinhibitor with anIC50of 0.21 μM in KRAS G12C/SOS1 binding assay. KRAS G12C inhibitor 57 inducescancercellapoptosis[1]. |
| IC50& Target[1] | KRAS(G12C) 0.21 μM (IC50, KRAS G12C/SOS1 binding assay) |
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体外研究
(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 (KRASp. 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 KRASp.G12C, MIA Paca2 cells harboring KRASp.G12C, H1975 cells harboring KRASp.WTand A549 cells harboring KRASp.G12S | | Concentration: | 0-10 μM | | Incubation Time: | 3 days | | Result: | Displayed favourable inhibitory activities on H358 cells and MIA Paca2 cells with the IC50values 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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体内研究
(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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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | Please store the product under the recommended conditions in the Certificate of Analysis. |
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