AMG-510 racemate |
| Catalog No.GC19546 |
Sotorasib (AMG-510) racemate is the racemate of Sotorasib (AMG-510). AMG-510 is a potent, orally bioavailable, and selective KRAS G12C covalent inhibitor with anti-tumor activity.
Products are for research use only. Not for human use. We do not sell to patients.
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.
Average Rating: 5 (Based on Reviews and 39 reference(s) in Google Scholar.)
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