Fulzerasib is an orally active KRAS G12C inhibitor that covalently binds to the cysteine residue on the protein, thereby inhibiting the growth of KRAS G12C mutant tumour cell lines, with an IC50 of 2–20 nM, and can be used to treat KRAS G12C mutant non-small cell lung cancer (NSCLC).

Method:
The mechanism of action of Fulzerasib on KRAS G12C was evaluated through in vitro enzymatic and cellular assays. The compound's ability to inhibit GDP/GTP nucleotide exchange (IC₅₀), reduce RAS-GTP levels (IC₅₀), and suppress downstream signaling molecule pERK (IC₅₀) was assessed. Additionally, its antiproliferative activity was tested in tumor cell lines harboring the KRAS G12C mutation.

Result:
Fulzerasib covalently inhibited GDP/GTP exchange on KRAS G12C (IC₅₀: 29 nM), locking KRAS in its inactive GDP-bound state (RAS-GTP IC₅₀: 74 nM) and blocking downstream signaling (pERK IC₅₀: 37 nM). Moreover, Fulzerasib effectively inhibited the proliferation of KRAS G12C-mutant tumor cell lines with IC₅₀ values ranging from 2 to 20 nM. [1]

Method:
The antitumor activity of Fulzerasib was evaluated in pancreatic cancer cell line xenograft models (MIA Paca-2 CDX), human lung adenocarcinoma xenograft models (NCI-H358 CDX), patient-derived colon adenocarcinoma xenograft models (SW837 CDX), and patient-derived lung cancer xenograft models (LU2529 PDX).

Result:
Fulzerasib demonstrated potent antitumor activity in multiple xenograft models of pancreatic cancer, lung adenocarcinoma, and colon cancer. [1]