Elisrasib (D3S-001) is a potent, selective, CNS-penetrable, covalent inhibitor of GDP-bound KRAS G12C inhibitor, decreases cellular active KRAS proteins in a dose-dependent manner (IC50=0.6 nM) in NCI-H358 cells.
D3S-001 is 58- and 130-fold more potent than sotorasib and adagrasib, respectively.
D3S-001 exhibits irreversible binding to GDP-bound KRAS G12C protein and limited or no binding to GTP-bound KRAS G12C protein.
D3S-001 demonstrates IC50 values of 0.5 and 0.3 nmol/L in NCI-H358 and MIA PaCa2 cells, respectively, which is a 38 to 86-fold increase in potency when compared with sotorasib or adagrasib.
D3S-001 inhibits cell growth with a median IC50 of 4.35 nmol/L in KRAS G12C-mutant cell lines, and a median IC50 > 10 μmol/L in cell lines without KRAS G12C mutation, D3S-001 exhibits high KRAS G12C allele-selective activity with markedly higher potency and selectivity compared with sotorasib and adagrasib.
D3S-001 (3, 10, 30, and 100 mg/kg, QD) inhibited KRAS signaling and tumor growth in NCI-H358 xenograft models, inhibited the phosphorylation of ERK1/2 and RSK.