AMG-510 racemate
(Synonyms: AMG-510(消旋体),AMG-510 racemate) 目录号 : GC19546
A covalent inhibitor of K-RasG12C
Cas No.:2252403-56-6
Sample solution is provided at 25 µL, 10mM.
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AMG-510 is the first KRAS G12C inhibitor in clinical development and leads to the regression of KRAS G12C tumors[1,3]. AMG-510 did not inhibit wild-type KRAS. AMG-510 irreversibly inhibits KRAS G12C by locking it in an inactive GDP-bound state[4].Amg-510 (Sotorasib) selectively reduced the viability of cell lines containing KRAS p.G12C mutation and showed antitumor activity.
In cellular assays, AMG-510 covalently modifies KRAS G12C and inhibits KRAS G12C signaling AMG-510 binds to the KRASG12C cysteine residue to lock the protein in its inactive form, inhibiting cell proliferation and promoting apoptosis[5].In two KRASG12C cell lines, NCI-H358 and MIA PaCa-2, AMG-510 almost completely inhibited p-ERK (IC50 ≈ 0.03 μM) after a 2h treatment and was 20-fold more potent than ARS-1620,AMG 510 also potently impaired cellular viability in both NCI-H358 and MIA PaCa-2 (IC50 ≈ 0.006 μM and 0.009 μM respectively[2]. Disrupting EFR3A or PI4KA reduces phosphatidylinositol-4-phosphate, phosphatidylserine, and KRAS levels at the plasma membrane, as well as oncogenic signaling and tumorigenesis, phenotypes rescued by tethering PI4KA to the plasma membrane.A selective PI4KA inhibitor augments the antineoplastic activity of the KRASG12C inhibitor AMG-510 [5].
In KRAS G12C tumor models, AMG-510 inhibited P-ERK in a dose-dependent manner at 2 h after treatment[2]. When evaluating toxicity, one preclinical study demonstrated that rats receiving 960mg sotorasib daily developed renal toxicity with necrosis and degeneration of kidney tubules, primarily at the proximal tubule[7].
References:
[1]: DOI: 10.1200/JCO.2019.37.15_suppl.3003 Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019) 3003-3003.Published online May 26, 2019.
[2]: Canon J, Rex K,et,al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019 Nov;575(7781):217-223. doi: 10.1038/s41586-019-1694-1. Epub 2019 Oct 30. PMID: 31666701.
[3]: Barbacid M. ras genes. Annu Rev Biochem. 1987;56:779-827. doi: 10.1146/annurev.bi.56.070187.004023. PMID: 3304147.
[4]: Lanman BA, Allen JR,et,al. Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors. J Med Chem. 2020 Jan 9;63(1):52-65. doi: 10.1021/acs.jmedchem.9b01180. Epub 2019 Dec 24. PMID: 31820981.
[5]: Adhikari H, Kattan WE,et,al. Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity. Nat Commun. 2021 Sep 9;12(1):5248. doi: 10.1038/s41467-021-25523-5. PMID: 34504076; PMCID: PMC8429657.
[6]: AMG 510 Shows Activity beyond NSCLC. Cancer Discov. 2020 Aug;10(8):1084-1085. doi: 10.1158/2159-8290.CD-NB2020-061. Epub 2020 Jun 15. PMID: 32540954.
[7]: Werner JA, Davies R,et,al. Mercapturate pathway metabolites of sotorasib, a covalent inhibitor of KRASG12C, are associated with renal toxicity in the Sprague Dawley rat. Toxicol Appl Pharmacol. 2021 Jul 15;423:115578. doi: 10.1016/j.taap.2021.115578. Epub 2021 May 15. PMID: 34004237.
AMG-510 是临床开发中的第一个 KRAS G12C 抑制剂，可导致 KRAS G12C 肿瘤消退[1,3]。 AMG-510 不抑制野生型 KRAS。 AMG-510 将 KRAS G12C 锁定在非活性 GDP 结合状态，从而不可逆地抑制它[4]。Amg-510 (Sotorasib) 选择性地降低含有 KRAS p.G12C 突变的细胞系的活力，并显示出抗肿瘤活性。
在细胞测定中，AMG-510 共价修饰 KRAS G12C 并抑制 KRAS G12C 信号传导 AMG-510 结合 KRASG12C 半胱氨酸残基以将蛋白质锁定在其非活性形式，抑制细胞增殖并促进细胞凋亡[5]。在两个 KRASG12C 中细胞系，NCI-H358 和 MIA PaCa-2，AMG-510 在处理 2 小时后几乎完全抑制 p-ERK (IC50 ≈ 0.03 μM)，比 ARS-1620 强 20 倍，AMG 510 也能显着损害细胞活力在 NCI-H358 和 MIA PaCa-2 中（IC50 ≈ 0.006 μM 和 0.009 μM 分别 [2]。破坏 EFR3A 或 PI4KA 可降低质膜上的磷脂酰肌醇 4-磷酸、磷脂酰丝氨酸和 KRAS 水平，以及致癌信号和肿瘤发生，通过将 PI4KA 拴在质膜上挽救表型。选择性 PI4KA 抑制剂增强了 KRASG12C 抑制剂 AMG-510 的抗肿瘤活性 [5]。
在 KRAS G12C 肿瘤模型中，AMG-510 在治疗后 2 小时以剂量依赖性方式抑制 P-ERK[2]。在评估毒性时，一项临床前研究表明，每天接受 960 毫克 sotorasib 的大鼠出现了肾毒性，主要是近端小管的坏死和肾小管变性[7]。
| Cell experiment [1]: | |
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Cell lines |
NCI-H358 and MIA PaCa-2 cell line |
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Preparation Method |
The phosphorylation of ERK was evaluated by treating cells with different concentrations of AMG-510 for 2 hours. |
|
Reaction Conditions |
10-4 -102 uM AMG-510 for 2h |
|
Applications |
In two KRASG12C cell lines, NCI-H358 and MIA PaCa-2, AMG-510 almost completely inhibited p-ERK (IC50 ≈ 0.03 µM) after a 2h treatment and was 20-fold more potent than ARS-1620. |
| Animal experiment [1]: | |
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Animal models |
Mice bearing MIA PaCa-2 T2 or CT-26 KRASG12C |
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Preparation Method |
tumours were treated orally with a single dose of vehicle or with the indicated doses of AMG-510 . Tumours were collected 2 h later or over time as indicated and levels of p-ERK were measured. |
|
Dosage form |
0.3-100mg/kg AMG-510 for 2-4h |
|
Applications |
In KRAS G12C tumor models, AMG-510 inhibited P-ERK in a dose-dependent manner at 2 h after treatment. |
|
References: [1]. Canon J, Rex K, et,al. The clinical KRAS(G12C) inhibitor AMG-510 drives anti-tumour immunity. Nature. 2019 Nov;575(7781):217-223. doi: 10.1038/s41586-019-1694-1. Epub 2019 Oct 30. PMID: 31666701. |
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| Cas No. | 2252403-56-6 | SDF | |
| 别名 | AMG-510(消旋体),AMG-510 racemate | ||
| Canonical SMILES | O=C(C=C)N1C[C@H](C)N(C2=NC(N(C3=C(C)C=CN=C3C(C)C)C4=C2C=C(F)C(C5=C(O)C=CC=C5F)=N4)=O)CC1 | ||
| 分子式 | C₃₀H₃₀F₂N₆O₃ | 分子量 | 560.59 |
| 溶解度 | 50 mg/ml in DMSO (Need ultrasonic); Insoluble in Water | 储存条件 | Store at -20°C, 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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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 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 |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet