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Published on: December 1, 2020
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K-Ras(G12D)-selective inhibitory peptides generated by random peptide T7 phage display technology
Kotaro Sakamoto1, Yusuke Kamada1, Tomoya Sameshima1
1Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.
Biochemical and Biophysical Research Communications
|February 4, 2017
Summary
Researchers developed KRpep-2d, a novel peptide inhibitor targeting the K-Ras(G12D) mutation. This selective inhibitor shows promise for developing new cancer therapies, addressing a long-standing challenge in oncology drug discovery.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Mutations in V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-Ras), specifically at Glycine 12 (e.g., G12D), are key drivers in numerous cancers.
- Despite over three decades since their discovery, effective inhibitors targeting mutated K-Ras remain unavailable, representing a significant unmet need in cancer therapy.
Purpose of the Study:
- To identify and develop novel, selective peptide inhibitors targeting the K-Ras(G12D) mutation.
- To evaluate the efficacy of these peptides in inhibiting K-Ras(G12D) activity and downstream signaling pathways.
Main Methods:
- Screening of T7 phage-displayed random peptide libraries against purified recombinant K-Ras(G12D).
- Rigorous subtraction of phages binding to wild-type K-Ras to ensure selectivity.
- Characterization of peptide binding and inhibition using Surface Plasmon Resonance (SPR) and enzyme assays.
- Optimization of lead peptide sequences and assessment of downstream effects on ERK phosphorylation and cancer cell proliferation.
Main Results:
- Identification of KRpep-2 as a consensus inhibitory peptide with >10-fold selectivity for K-Ras(G12D) over wild-type K-Ras.
- Optimized peptide KRpep-2d demonstrated potent inhibition of K-Ras(G12D) enzyme activity (IC50 = 1.6 nM).
- KRpep-2d significantly suppressed downstream ERK phosphorylation and proliferation of A427 cancer cells at 30 μM.
Conclusions:
- This study reports the first K-Ras(G12D)-selective inhibitor, KRpep-2d.
- The findings provide a foundation for the development of targeted K-Ras(G12D) therapies.
- This work contributes to advancing the therapeutic strategies against K-Ras-driven cancers.
