Selective apoptosis-inducing activity of synthetic hydrocarbon-stapled SOS1 helix with d-amino acids in H358 cancer cells expressing KRAS G12C .

Lung cancer is one of the most malignant tumors with the highest morbidity and mortality. Most of them are non-small cell lung cancer (NSCLC). KRASG12C gene mutation is an important driving factor for NSCLC. However, the development of high-affinity inhibitors targeting KRASG12C mutants remains a daunting challenge. Here, we report the design and development of a series of hydrocarbon-stapled peptides containing d-amino acids to mimic the alpha helix of SOS1. D-hydrocarbon-stapled peptides maintain good alpha helix structure and bind to KRASG12C with high affinity. Subsequent anti-proliferation experiments indicated that D-hydrocarbon-stapled peptide 5 inhibited the proliferation of NSCLC H358 cells carrying KRASG12C . However, it showed no significant anti-proliferative effect on KRASG12S -positive A549 cells, suggesting that peptide 5 selectively inhibits KRASG12C -driven tumor cells. D-hydrocarbon-stapled peptide 5 could also cause the cell cycle of H358 cells to arrest in the G2 /M phase and induce apoptosis. No significant cell arrest and apoptosis were observed in A549 cells treated by peptide 5. In summary, the introduction of d-amino acids could improve the affinity and cell selectivity of hydrocarbon peptides. We hope that peptides containing D-form amino acids can provide strategies for further optimization of the KRASG12C /SOS1 inhibitor.