RNK08954 is a potent, selective, non-covalent and orally bioavailable KRAS G12D inhibitor, binds primarily to the inactive KRAS G12D (GDP-bound) with SPR KD of 39.5 pM and to the active KRAS G12D (GTP-bound) form with KD of 12.2 nM.
RNK08954 shows overall higher binding affinity to KRAS WT, KRAS G12C and KRAS G12V proteins.
RNK08954 showsconcentration-dependent inhibition of p-ERK1/2 levels in human pancreatic adenocarcinoma cell line SW1990, performs better than MRTX1133, also demonstrates time- and concentration-dependent inhibition of p-AKT level.
RNK08954 exhibits potent inhibition with IC50 ranging from 2.6 nM to 49.5 nM in human tumor cells with KRAS G12D mutation and shows selectivity against cells with KRAS WT and other non-G12D KRAS mutations, with IC50 value of RNK08954 higher than 300 nM.
RNK08954 significantly inhibits cell viability in cells with KRAS G12D mutation with median IC50 of 10.8 nM in CTG assays in Ba/F3 cell lines.
RNK08954 induces cell cycle arrest in G0/G1 phase in a dose-dependent manner, and lead to cell death.
RNK08954 exhibits anti-tumor activity in KRAS G12D mutant CDX and PDX models, inducing 70% tumor regression in mice bearing GP2d xenograft administered 60 mg/kg (QD), 100% tumor regression at the 100 mg/kg twice a day (BID) in Panc 04.03 xenograft.