AUTHOR=Xie Chun , Li Ying , Li Lan-Lan , Fan Xing-Xing , Wang Yu-Wei , Wei Chun-Li , Liu Liang , Leung Elaine Lai-Han , Yao Xiao-Jun 

TITLE=Identification of a New Potent Inhibitor Targeting KRAS in Non-small Cell Lung Cancer Cells

JOURNAL=Frontiers in Pharmacology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2017.00823

DOI=10.3389/fphar.2017.00823

ISSN=1663-9812

ABSTRACT=<p>KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is an oncogenic driver with mutations in 30% of non-small cell lung cancer (NSCLC). However, there is no effective clinical drug even though it has been identified as an oncogene for 30 years. In this study, we identified a small molecule inhibitor compound 0375-0604 targeting KRAS by using molecular docking based virtual screening approach. Compound 0375-0604 had a good binding affinity to KRAS <italic>in vitro</italic> and exhibited cytotoxicity in oncogenic KRAS expressing NSCLC cell lines. Further mechanism study showed that compound 0375-0604 can block the formation of the complex of guanosine triphosphate (GTP) and KRAS <italic>in vitro</italic>. In addition, compound 0375-0604 inhibited KRAS downstream signaling pathway RAF/MEK/ERK and RAF/PI3K/AKT. Finally, we also found that this compound can inhibit the cell growth through G2/M cell cycle arrest and induce apoptosis on the NSCLC cell lines harboring KRAS mutation. Therefore, compound 0375-0604 may be considered as a potential KRAS inhibitor for treatment of NSCLC carrying KRAS oncogene.</p>