Identification of novel peptide inhibitors for the KRas-G12C variant to prevent oncogenic signaling

Kirsten rat sarcoma viral oncogene homolog (KRas) activating mutations are common in solid tumors, accounting for 90%, 45%, and 35% of pancreatic, colorectal, and lung cancers (LC), respectively. Each year, nearly 150k new cases (both men and women) of KRas-mutated malignancies are reported in the United States. NSCLC (non-small cell lung cancer) accounts for 80% of all LC cases. KRas mutations are found in 15% to 25% of NSCLC patients. The main cause of NSCLC is the KRas-G12C mutation. The drugs Sotorasib and Adagrasib were recently developed to treat advanced NSCLC caused by the KRas-G12C mutation. Most patients do not respond to KRas-G12C inhibitors due to cellular, molecular, and genetic resistance. Because of their safety, efficacy, and selectivity, peptide inhibitors have the potential to treat newly developing KRas mutations. Based on the KRas mutations, peptide inhibitors that are highly selective and specific to individual lung cancers can be rationally designed. The current study uses an alanine and residue scanning approach to design peptide inhibitors for KRas-G12C based on the known peptide. Our findings show that substitution of F3K, G11T, L8C, T14C, K13D, G11S, and G11P considerably enhances the binding affinity of the novel peptides, whereas F3K, G11T, L8C, and T14C peptides have higher stability and favorable binding to the altered peptides. Overall, our study paves the road for the development of potential therapeutic peptidomimetics that target the KRas-G12C complex and may inhibit the KRas and SOS complex from interacting.Communicated by Ramaswamy H. Sarma.