Sotorasib |
| رقم الكتالوجGC62238 |
Sotorasib (AMG-510) هو مثبط تساهمي KRAS G12C من الدرجة الأولى في فئته ومتوفر بيولوجيًا انتقائيًايثبط Sotorasib بشكل لا رجعة فيه KRAS G12C عن طريق قفله في حالة غير نشطة مرتبطة بالناتج المحلي الإجماليSotorasib هو أول مثبط KRAS G12C في التطور السريري ويؤدي إلى تراجع أورام KRAS G12C
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Cas No.: 2296729-00-3
Sample solution is provided at 25 µL, 10mM.
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Sotorasib (AMG510) is a potent covalent inhibitor of KRASG12C (Glycine at position 12 of KRAS protein mutated to cysteine) that specifically and irreversibly inhibits KRASG12C by locking KRASG12C in an inactive GDP-bound state. Sotorasib is a chiral compound with potential anti-tumor activity [1].
In NCI-H358 and MIA PaCa-2 cells, Sotorasib almost completely inhibited p-ERK (IC50 is 0.03μM) levels and significantly inhibited cell viability, with IC50 values of 0.006μM and 0.009μM respectively [2]. Using different concentrations of Sotorasib to treat KRAS mutant cell line H23 (1μM), wild-type KRAS cell line H522 (15μM) and A549 cells (25μM) can inhibit cell viability and induce cell apoptosis [3].
In the KRASG12C tumor model, Sotorasib (30-100mg/kg) inhibited p-ERK in a dose-dependent manner 2 hours after treatment. In mice xenografted with human tumor cells, Sotorasib (3, 10, 30 and 100mg/kg) significantly inhibited the growth of MIA PaCa-2 T2 and NCI-H358 tumors at all doses and at 100mg/kg Tumor regression was observed at the dose [2]. Sotorasib (25mg/kg) significantly reduced the volume, weight, and size of mouse tumors in the MIA PaCa-2 tumor xenograft model without any evidence of organ toxicity or metastatic spread[4].
References:
[1] Fakih M, O'Neil B, Price T J, et al. Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors[J]. 2019.
[2] Canon J, Rex K, Saiki A Y, et al. The clinical KRAS (G12C) inhibitor AMG 510 drives anti-tumour immunity[J]. Nature, 2019, 575(7781): 217-223.
[3] Barrios-Bernal P, Lucio-Lozada J, Ramos-Ramírez M, et al. A Novel Combination of Sotorasib and Metformin Enhances Cytotoxicity and Apoptosis in KRAS-Mutated Non-Small Cell Lung Cancer Cell Lines through MAPK and P70S6K Inhibition[J]. International Journal of Molecular Sciences, 2023, 24(5): 4331.
[4] Khan H Y, Nagasaka M, Aboukameel A, et al. Anticancer Efficacy of KRASG12C Inhibitors Is Potentiated by PAK4 Inhibitor KPT9274 in Preclinical Models of KRAS G12C-Mutant Pancreatic and Lung Cancers[J]. Molecular Cancer Therapeutics, 2023, 22(12): 1422-1433.
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