Apoptosis-inducing activity of synthetic hydrocarbon-stapled peptides in H358 cancer cells expressing KRASG12C

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 occupying 80% 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 KRAS-mediated RAF/MEK/ERK signaling, which was verified from the perspective of genomics and proteomics. Peptide 3 also exhibited strong anti-trypsin and anti-chymotryps in 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. (C) 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

Automated summary

Lung cancers, particularly NSCLC driven by KRAS(G12C) gene mutations, are a major threat to human health. A newly synthesized peptide drug showed promising anti-tumor effects and stability, targeting KRAS-mutated lung cancer cells and disrupting KRAS-mediated signaling pathways. This research provides a structural optimization strategy for KRAS(G12C) peptide inhibitors in cancer therapy.