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Peptides That Block RAS-p21 Protein-Induced Cell Transformation
Matthew R Pincus1, Bo Lin1,2, Purvi Patel1
1Department of Pathology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
Biomedicines
|February 25, 2023
Summary
Targeting oncogenic RAS-p21 proteins with peptides and small molecules shows promise for treating various cancers. New FDA-approved drugs offer personalized medicine options for specific RAS mutations, with ongoing research for broader applications.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Mutations in RAS-p21 protein, particularly at Gly 12 and Gln 61, lead to oncogenic transformation and drive various cancers, including pancreatic, colon, and non-small cell lung cancer (NSCCL).
- RAS-p21 is a G-protein crucial for cell signaling, and its aberrant activation by mutations results in uncontrolled cell proliferation.
Purpose of the Study:
- To review and discuss diverse strategies for designing peptides and small molecules that selectively inhibit oncogenic RAS-p21.
- To highlight recent advancements in targeted therapies for RAS-driven cancers and explore future directions.
Main Methods:
- Molecular simulations to identify critical effector domains for peptide targeting.
- High-throughput screening of peptide and small molecule libraries to find inhibitors.
- Bioinformatic approaches to discover molecules that dock to specific RAS-p21 domains.
- Development of cell-penetrating peptides (CPPs) conjugated to antibodies for targeted delivery.
Main Results:
- Several peptide inhibitors (PNC-1, PNC-2, PNC7) and small molecules have been identified that target specific RAS-p21 mutations.
- FDA-approved drugs like AMG510 and MRTX849 effectively target the G12C mutant RAS-p21, stabilizing its inactive GDP-bound form.
- Research is expanding to address other common RAS mutations (G12D) and develop more general anti-oncogenic agents.
Conclusions:
- Targeted therapies against oncogenic RAS-p21 represent a significant advancement in personalized cancer medicine.
- The development of selective inhibitors offers new hope for patients with RAS-driven malignancies.
- Continued research is essential to overcome challenges posed by diverse RAS mutations and improve treatment outcomes.
Keywords:
RAS-p21 proteinamino acid substitutionsblockade of oncogenic proteincell transformationmutant proteinoncogenic formspeptidessmall moleculesMore Related Videos
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