KRAS G12C inhibitor compound 8 is a potent, specific KRAS G12C dual inhibitor with IC50 of 10 nM (GDP Exchange Inhibition) and 133 nM (RAS/RAF Disruption), covalently modifies both KRAS G12C inactive and active states.
Compound 8 is a rapid inhibitor of both the GDP-bound inactive state KRAS G12C (kinact/KI >79,000 M-1s-1) and GMPPNP-bound active state KRAS G12C (kinact/KI >8,000 M-1s-1).
Compound 8 shows comparable pERK potency (IC50: 0.4 nM) to divarasib (IC50: 0.3 nM).
Compound 8 inhibits cellular proliferation in MIA PaCa-2, a KRAS G12C mutant cell line, with IC50 of 1.6 nM.
Compound 8 shows robust and potent activity in a panel of KRAS G12C mutant cell lines with cell line sensitivity profile similar to KRAS G12C inactive state-selective inhibitor divarasib.
Compound 8 showsselectivity for the Cys12 of KRAS G12C over the majority of other peptides identified, including Cys 80 of KRAS and NRAS.
(150 mg/kg twice daily (BID)) demonstated tumor growth inhibition of 88% in KRASG12C-mutant NSCLC patient derived xenograft (PDX) model.