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]。