Selective apoptosis-inducing activity of synthetic hydrocarbon-stapled SOS1 helix with d-amino acids in H358 cancer cells expressing KRASG12C.
Xu LL, Li CC, An LY, Dai Z, Chen XY, You QD, Hu C, Di B.
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.