Apoptosis-inducing activity of synthetic hydrocarbon-stapled peptides in H358 cancer cells expressing KRAS^(G12C)

摘要

Lung cancers are the leading cause of cancer deaths worldwide and pose a grave threat to human life and health.Non-small cell lung cancer (NSCLC) is the most frequent malignancy occupying80%of all lung cancer subtypes.Except for other mutations (e.g.,KRAS^(G12V/D)) that are also vital for the occurrence,KRAS^(G12C) gene mutation is a significant driving force of NSCLC,with a prevalence of approximately 14% of all NSCLC patients.However,there are only a few therapeutic drugs targeting KRAS^(G12C) mutations currently.Here,we synthesized hydrocarbon-stapled peptide 3 that was much shorter and more stable with modest KRAS^(G12C) binding affinity and the same anti-tumor effect based on the a-helical peptide mimic SAH-SOS1_(A).The stapled peptide 3 effectively induced G2/M arrest and apoptosis,inhibiting cell growth in KRAS-mutated lung cancer cells via disrupting the KRASmediated RAF/MEK/ERK signaling,which was verified from the perspective of genomics and proteomics.Peptide 3 also exhibited strong anti-trypsin and anti-chymotrypsin abilities,as well as good plasma stability and human liver microsomal metabolic stability.Overall,peptide 3 retains the equivalent anti-tumor activity of SAH-SOS1_(A) but with improved stability and affinity,superior to SAH-SOS1_(A).Our work offers a structural optimization approach of KRAS^(G12C) peptide inhibitors for cancer therapy.