ACA22 is a small molecule KRAS inhibitor, inhibits KRAS-mediated signal transduction in cells expressing wild type (WT) and G12D mutant KRAS.
ACA22 binds to guanosine 5′-β,γ-imidophosphate, GNP (a non-hydrolysable GTP analogue)-bound WT and G12D, G13D, and Q61H KRAS at pocket p1 with KD 3-16 uM.
ACA22 shows affinity for WT GNP-KRAS (KD=3 uM), 75-fold stronger than that for the GDP-bound form (GDP-KRAS WT, Kd=225 uM).
ACA22 inhibits WT KRAS more robustly than mutant KRAS.
ACA22 has no effect on intrinsic or GEF-mediated nucleotide exchange reactions of KRAS, also has no effect on KRAS-effector interactions.
