AMG 510 |Covalent KRAS^G12C Inhibitor

AMG 510 (2296729-00-3; Sotorasib) is a potent (IC₅₀’s = 6 nM NCI-H358; 9 nM MIA PaCa-2) covalent KRAS^G12C inhibitor.^1,2 It significantly inhibited tumor growth in NCI-H358 and MIA PaCa-2 cell lines as well as CT-26 tumors (mouse syngeneic model) and caused tumor regression at higher doses.¹ AMG 510 improved the efficacy of various other chemotherapeutic agents including inhibitors of HER kinases, EGFR, SHP2, PI3K, AKT, and MEK ^1,3 and synergized with  immune checkpoint reagents¹. FDA approved for use in KRAS^G12C-positive non-small cell lung cancer. AMG 510 displayed efficacy alone^4,5 and in combination⁵ with trametinib and/or buparlisib in pancreatic ductal adenocarcinoma cell lines.

References/Citations:

1. Canon et al. (2019), The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumor immunity; Nature 575 217
2. Lanman et al. (2020); Discovery of a Covalent Inhibitor of KRAS^G12C (AMG 510) for the Treatment of Solid Tumors, J. Med. Chem., 63 52
3. Barrios-Bernal et al. (2023); 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, Int. J. Mol. Sci., 24 4331
4. Strickler et al. (2023); Sotorasib in KRASp.G12C-Mutated Advanced Pancreatic Cancer, N. Engl. J. Med., 388 33
5. Ma et al. (2022); Inhibition of KRAS, MEKI, and PI3K Demonstrate Synergistic Anti-Tumor Effects in Pancreatic Ductal Adenocarcinoma Cell Lines, Cancers (Basel), 14 4467