Sotorasib
(Synonyms: 索托拉西布; AMG-510) 目录号 : GC62238
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。
Cas No.:2296729-00-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
Cell lines | Sotorasib-resistant parental cell line (MIA PaCa-R) and Sotorasib-sensitive parental cell line (MIA PaCa-2) |
Preparation Method | Cell viability was assayed by MTT assay after incubating different concentrations of Sotorasib with cells for 72 h. |
Reaction Conditions | 0-1.6μM, 72 h |
Applications | Sotorasib inhibited MIA PaCa-R and MIA PaCa-2 cell viability with IC50 of 2.789μM and 66.17nM, respectively. |
| Animal experiment [1]: | |
Animal models | MIA PaCa-2 cell-derived tumor xenograft model |
Preparation Method | Hormonal mice were randomized into 4 groups of 6 mice each to receive either vector or or KPT9274 (100mg/kg every day × 5×3 weeks), or Sotorasib (25mg/kg every day × 5×3 weeks), or their combination by oral gavage. |
Dosage form | 25mg/kg, Five times a week for three weeks, i.g. |
Applications | Sotorasib significantly reduced tumor volume, tumor weight and tumor size. |
References: [1] 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) 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]。
| Cas No. | 2296729-00-3 | SDF | |
| 别名 | 索托拉西布; AMG-510 | ||
| 分子式 | C30H30F2N6O3 | 分子量 | 560.59 |
| 溶解度 | DMSO : 50 mg/mL (89.19 mM; Need ultrasonic)；Water : 33.33 mg/mL (59.46 mM; ultrasonic and adjust pH to 11 with NaOH) | 储存条件 | Store at -20°C,protect from light, stored under nitrogen |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.7838 mL | 8.9192 mL | 17.8383 mL |
| 5 mM | 0.3568 mL | 1.7838 mL | 3.5677 mL |
| 10 mM | 0.1784 mL | 0.8919 mL | 1.7838 mL |
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Sotorasib for Lung Cancers with KRAS p.G12C Mutation
N Engl J Med 2021 Jun 24;384(25):2371-2381.PMID:34096690DOI:10.1056/NEJMoa2103695.
Background: Sotorasib showed anticancer activity in patients with KRAS p.G12C-mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non-small-cell lung cancer (NSCLC). Methods: In a single-group, phase 2 trial, we investigated the activity of Sotorasib, administered orally at a dose of 960 mg once daily, in patients with KRAS p.G12C-mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to Sotorasib therapy. Results: Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval [CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in STK11, KEAP1, or TP53. Conclusions: In this phase 2 trial, Sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated KRAS p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).
KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors
N Engl J Med 2020 Sep 24;383(13):1207-1217.PMID:32955176DOI:10.1056/NEJMoa1917239.
Background: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C. Methods: We conducted a phase 1 trial of Sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received Sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Results: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. Conclusions: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).
Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial
Lancet Oncol 2022 Jan;23(1):115-124.PMID:34919824DOI:10.1016/S1470-2045(21)00605-7.
Background: Sotorasib, a specific, irreversible KRASG12C protein inhibitor, has shown monotherapy clinical activity in KRASG12C-mutated solid tumours, including colorectal cancer, in the CodeBreaK100 phase 1 trial. We aimed to investigate the activity and safety of Sotorasib in phase 2 of the trial. Methods: In this single-arm, phase 2 trial, adult patients with KRASG12C-mutated advanced solid tumours were enrolled, from 59 medical centres in 11 countries, if they were aged 18 years or older, had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Only data for patients with colorectal cancer, enrolled at 33 medical centres in nine countries, are presented from this basket trial. To be enrolled, the patients had to have progressed after receiving fluoropyrimidine, oxaliplatin, and irinotecan treatment. These patients were administered 960 mg Sotorasib orally once per day until disease progression, development of unacceptable side-effects, withdrawal of consent, or death. The primary endpoint was objective response (complete or partial response) as assessed by blinded independent central review. Response was evaluated in patients who received at least one dose of Sotorasib and had at least one measurable lesion at baseline; safety was evaluated in patients who received at least one dose of Sotorasib. This analysis is a prespecified analysis triggered by the phase 2 colorectal cancer cohort. This study is registered with ClinicalTrials.gov, NCT03600883, and is active but no longer recruiting. Findings: On March 1, 2021, at data cutoff, 62 patients with KRASG12C-mutant colorectal cancer had been enrolled between Aug 14, 2019, and May 21, 2020, and had received at least one dose of Sotorasib monotherapy. Objective response was observed in six (9·7%, 95% CI 3·6-19·9) of 62 patients, all with partial response. Treatment-related adverse events at grade 3 occurred in six (10%) patients, the most common of which was diarrhoea (two [3%] of 62 patients), and at grade 4 occurred in one (2%) patient (blood creatine phosphokinase increase); no fatal events were recorded. Serious treatment-related adverse events occurred in two (3%) patients (back pain and acute kidney injury). Interpretation: Although the 9·7% overall response rate did not reach the benchmark, oral administration of Sotorasib once per day showed modest anti-tumour activity and manageable safety in these heavily pretreated chemorefractory patients. Sotorasib is under evaluation in combination with other therapeutics to increase potential activity and overcome potential resistance mechanisms. Funding: Amgen.
Sotorasib: First Approval
Drugs 2021 Sep;81(13):1573-1579.PMID:34357500DOI:10.1007/s40265-021-01574-2.
Sotorasib (LUMAKRAS™) is a RAS GTPase family inhibitor being developed by Amgen for the treatment of solid tumours with KRAS mutations, including non-small cell lung cancer (NSCLC) and colorectal cancer. In May 2021, Sotorasib was granted accelerated approval by the US FDA for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy. This article summarizes the milestones in the development of Sotorasib leading to this first approval for KRAS G12C-mutated NSCLC.
Sotorasib in KRAS p.G12C-Mutated Advanced Pancreatic Cancer
N Engl J Med 2023 Jan 5;388(1):33-43.PMID:36546651DOI:10.1056/NEJMoa2208470.
Background: KRAS p.G12C mutation occurs in approximately 1 to 2% of pancreatic cancers. The safety and efficacy of Sotorasib, a KRAS G12C inhibitor, in previously treated patients with KRAS p.G12C-mutated pancreatic cancer are unknown. Methods: We conducted a single-group, phase 1-2 trial to assess the safety and efficacy of Sotorasib treatment in patients with KRAS p.G12C-mutated pancreatic cancer who had received at least one previous systemic therapy. The primary objective of phase 1 was to assess safety and to identify the recommended dose for phase 2. In phase 2, patients received Sotorasib at a dose of 960 mg orally once daily. The primary end point for phase 2 was a centrally confirmed objective response (defined as a complete or partial response). Efficacy end points were assessed in the pooled population from both phases and included objective response, duration of response, time to objective response, disease control (defined as an objective response or stable disease), progression-free survival, and overall survival. Safety was also assessed. Results: The pooled population from phases 1 and 2 consisted of 38 patients, all of whom had metastatic disease at enrollment and had previously received chemotherapy. At baseline, patients had received a median of 2 lines (range, 1 to 8) of therapy previously. All 38 patients received Sotorasib in the trial. A total of 8 patients had a centrally confirmed objective response (21%; 95% confidence interval [CI], 10 to 37). The median progression-free survival was 4.0 months (95% CI, 2.8 to 5.6), and the median overall survival was 6.9 months (95% CI, 5.0 to 9.1). Treatment-related adverse events of any grade were reported in 16 patients (42%); 6 patients (16%) had grade 3 adverse events. No treatment-related adverse events were fatal or led to treatment discontinuation. Conclusions: Sotorasib showed anticancer activity and had an acceptable safety profile in patients with KRAS p.G12C-mutated advanced pancreatic cancer who had received previous treatment. (Funded by Amgen and others; CodeBreaK 100 ClinicalTrials.gov number, NCT03600883.).