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.
Sotorasib（AMG510）是一种有效的KRASG12C（KRAS蛋白12位的甘氨酸突变为半胱氨酸）共价抑制剂，通过将KRASG12C锁定在无活性的GDP结合状态，特异性且不可逆地抑制KRASG12C。Sotorasib是一种手性化合物，具有潜在的抗肿瘤活性[1]。
在NCI-H358和MIA PaCa-2细胞中，Sotorasib几乎完全抑制了p-ERK（IC50为0.03μM）水平，并且显著抑制细胞活力，IC50值分别为0.006μM和0.009μM[2]。使用不同浓度的Sotorasib处理KRAS突变细胞系H23（1μM）、野生型KRAS细胞系H522（15μM）和A549细胞（25μM），可抑制细胞活力，诱导细胞凋亡[3]。
在KRASG12C肿瘤模型中，Sotorasib（30-100mg/kg）在治疗后2小时以剂量依赖性方式抑制p-ERK。在人类肿瘤细胞异种移植的小鼠中，Sotorasib（3、10、30和100mg/kg）在所有剂量下均能显著抑制MIA PaCa-2 T2和NCI-H358肿瘤的生长，并且在100mg/kg剂量下观察到肿瘤的消退[2]。Sotorasib（25mg/kg）可明显减小MIA PaCa-2肿瘤异种移植模型中小鼠肿瘤的体积、重量和大小，并且未发现任何器官毒性或转移扩散迹象[4]。