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Identification of a New Potent Inhibitor Targeting KRAS in Non-small Cell Lung Cancer Cells
Chun Xie1, Ying Li1, Lan-Lan Li2
1State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China.
Abstract:
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.
Insights
A novel small molecule inhibitor, compound 0375-0604, effectively targets KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutations in non-small cell lung cancer (NSCLC). This compound shows potential for treating KRAS-mutated NSCLC by inhibiting cell growth and inducing apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is a critical oncogenic driver in 30% of non-small cell lung cancer (NSCLC) cases.
- Despite its identification as an oncogene 30 years ago, effective clinical drugs targeting KRAS remain unavailable.
- Targeting KRAS mutations presents a significant unmet need in NSCLC treatment.
Purpose of the Study:
- To identify and characterize a novel small molecule inhibitor targeting oncogenic KRAS.
- To evaluate the efficacy and mechanism of action of compound 0375-0604 in KRAS-mutated NSCLC cell lines.
- To explore the potential of compound 0375-0604 as a therapeutic agent for NSCLC.
Main Methods:
- Molecular docking based virtual screening was employed to identify potential KRAS inhibitors.
- In vitro binding affinity assays and cytotoxicity assessments were performed.
- Mechanism of action studies included evaluating guanosine triphosphate (GTP)-KRAS complex formation and downstream signaling pathways (RAF/MEK/ERK and RAF/PI3K/AKT).
- Cell cycle analysis and apoptosis assays were conducted on NSCLC cell lines.
Main Results:
- Compound 0375-0604 demonstrated significant binding affinity to KRAS and exhibited cytotoxicity in KRAS-expressing NSCLC cell lines.
- The compound effectively blocked KRAS-GTP complex formation in vitro.
- Compound 0375-0604 inhibited key downstream signaling pathways, including RAF/MEK/ERK and RAF/PI3K/AKT.
- Treatment with compound 0375-0604 induced G2/M cell cycle arrest and apoptosis in NSCLC cells harboring KRAS mutations.
Conclusions:
- Compound 0375-0604 is a promising small molecule inhibitor targeting KRAS.
- This inhibitor effectively disrupts KRAS signaling and downstream pathways, leading to cell growth inhibition and apoptosis.
- Compound 0375-0604 represents a potential therapeutic candidate for non-small cell lung cancer with KRAS mutations.
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