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...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.展开更多
基金supported by projects of the National Natural Science Foundation of China(81803354 and 81773693)the Natural Science Foundation of Jiangsu Province of China(BK20180564)+2 种基金the Fundamental Research Funds for the Central Universities(2632021ZD13,China)Double First-Class Innovation Team of China Pharmaceutical University(CPU2018GY02,China)the Program for Outstanding Scientific and Technological Innovation Team of Jiangsu Higher Education(YY20180315004,China)
文摘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.
