Discovery of a novel drug using lipid-based formulation targeting G12D-mutated KRAS4B through non-covalent bonds

Abstract

AbstractOne of the most common drivers in human cancer is KRAS4B. In recent years, the promising KRAS targeted drug development has attracted significant new research interest and reignited the field of RAS therapeutics. To signal, oncogenic KRAS4B not only requires a sufficient nucleotide exchange, but also needs to recruit effectors by exposing its effector-binding sites while anchoring to plasma membrane where KRAS4B-mediated signaling events occur. Phosphodiesterase-δplays an important role in sequestering KRAS4B from the cytoplasm and targeting it to cellular membranes. In this work, we have designed a drug LIG1 using lipid-based formulation to directly target both the switch-IIpocket of KRAS4B-G12D and phosphodiesterase-δ. LIG1 was found to lock KRAS4B in its GDP-bound state while the effector-binding domain is blocked by the interface of the plasma membrane which hinders the nucleotide exchange while simultaneously it can affect the GTP-bound KRAS4B to shift from an active state to its inactive state. LIG1 is also observed to stably accommodate itself in the prenyl-binding pocket of phosphodiesterase-δwhich impairs KRAS4B enrichment at the membrane and suppress the proliferation of KRAS4B-dependent cancer cells. In this work we report a drug based on lipid-based formulation that can foster drug discovery efforts for the targeting of oncogenes of the RAS family and beyond.