TH-Z835 is a potent, mutant selective KRAS (G12D) inhibitor with IC50 of 1.6 uM.
TH-Z835 binds to both GDP-bound and GMPPNP-bound KRAS G12D with similar affinities, efficiently disrupt KRAS–CRAF interaction, but do not bind to wide type and G12C mutant KRAS.
TH-Z835 reduced the pERK level in PANC-1 cells with an IC50 <2.5 uM, exhibited anti-proliferative effects for KRAS(G12D)-bearing pancreatic cancer cell lines PANC-1 and KPC with IC50 of <0.5 uM, induced arrest at the G1 phase of the cell cycle.
TH-Z835 displayed anti-tumor effects alone and in combination with anti-PD-L1 antibody in xenograft pancreatic tumor models.
