Identification of a new potent inhibitor targeting KRAS in non-small cell lung cancer cells

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

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


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 in vitro 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 in vitro. 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.

Original languageEnglish (US)
Article number823
JournalFrontiers in Pharmacology
Issue numberNOV
StatePublished - Nov 14 2017
Externally publishedYes


  • KRAS
  • Molecular docking
  • Small molecule inhibitor

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)


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