Sotorasib (AMG-510) is an orally active and selective covalent inhibitor of KRAS G12C. Sotorasib binds to the GDP state of the inactive conformation of KRAS G12C and inhibits KRAS and its downstream signaling. Sotorasib exhibits inhibitory activity against KRAS G12C mutant tumors.

METHODS: Twenty-two tumor cells were treated with Sotorasib (0-10 μM) for 72 h. Cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Assay kit.
RESULTS: Sotorasib impaired the growth of all KRAS G12C cell lines except SW1573, with IC50 values ranging from 0.004-0.032 μM. non-KRAS G12C cell lines were sensitive to Sotorasib, with an IC50 >7.5 μM. [1]
METHODS: KRAS G12C mutant tumor cells were treated with Sotorasib (100 nM) for 4-72 h, and the expression levels of target proteins were detected using Western Blot method.
RESULTS: Sotorasib rapidly inhibited KRAS downstream signaling, but p-ERK levels returned to 75% of the baseline level at 72 h. Sotorasib was also shown to rapidly inhibit KRAS downstream signaling. [2]

METHODS: To assay antitumor activity in vivo, Sotorasib (3-100 mg/kg) was orally administered once daily for four weeks to athymic nude mice bearing the human pancreatic cancer tumor MIA PaCa-2 T2 or the human lung cancer tumor NCI-H358.
RESULTS: Sotorasib significantly inhibited the growth of MIA PaCa-2 T2 and NCI-H358 tumors at all doses, and tumor regression was observed at higher doses. [1]
METHODS: To assay antitumor activity in vivo, Sotorasib (30 mg/kg in 0.5% sodium carboxymethylcellulose, administered by gavage once daily) and Cisplatin (4 mg/kg in 0.9% saline, intraperitoneally every two days) were administered to Balb/C nude mice harboring human lung cancer tumors.
RESULTS: Tumor shrinkage in the combination group was more than twice that of the single-administration group. [3]