RLY01 is a potent small-molecule REGγ-20S proteasome inhibitor, has affinity (KD) of 11.6 uM for 20S proteasome, blocks its degradation function, ultimately leading to cancer cell death.
RLY01 binds to and occupies the REGγ-bound pocket, suppressing REGγ-dependent 20S proteasome activity.
RLY01 blocks the degradation function of the REGγ-20S proteasome in a REGγ-dependent manner.
RLY01 blocks the growth of pan-KRAS–mutant tumors in vitro.
RLY01 increases the levels of the apoptosis-related proteins cleaved PARP (Cl-PARP) and cleaved caspase-3 (Cl-caspase-3) in KRAS-mutant cells in a concentration-dependent and REGγ-dependent manner, with no substantial effect on apoptosis in HCT116-REGγ-KO cells.
RLY01 treatment (25-50 mg/kg) effectively suppressed tumor growth in KRAS-mutant cancer models and lung cancer organoids.
The combination of RLY01 and the KRASG12C inhibitor AMG510 exhibited enhanced antitumor efficacy in KRASG12C cancer cells.