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Inhibitors of Ras-SOS Interactions
Shaoyong Lu1, Hyunbum Jang2, Jian Zhang3
1Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200025, China.
Abstract:
Activating Ras mutations are found in about 30 % of human cancers. Ras activation is regulated by guanine nucleotide exchange factors, such as the son of sevenless (SOS), which form protein-protein interactions (PPIs) with Ras and catalyze the exchange of GDP by GTP. This is the rate-limiting step in Ras activation. However, Ras surfaces lack any evident suitable pockets where a molecule might bind tightly, rendering Ras proteins still 'undruggable' for over 30 years. Among the alternative approaches is the design of inhibitors that target the Ras-SOS PPI interface, a strategy that is gaining increasing recognition for treating Ras mutant cancers. Herein we focus on data that has accumulated over the past few years pertaining to the design of small-molecule modulators or peptide mimetics aimed at the interface of the Ras-SOS PPI. We emphasize, however, that even if such Ras-SOS therapeutics are potent, drug resistance may emerge. To counteract this development, we propose "pathway drug cocktails", that is, drug combinations aimed at parallel (or compensatory) pathways. A repertoire of classified cancer, cell/tissue, and pathway/protein combinations would be beneficial toward this goal.
Insights
Targeting the Ras-Son of Sevenless (SOS) protein-protein interaction (PPI) is a promising strategy for treating cancers with Ras mutations. Developing drug cocktails that target compensatory pathways is proposed to overcome potential drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Activating Ras mutations drive approximately 30% of human cancers.
- Ras proteins are historically challenging to target directly due to their smooth surface, earning them the "undruggable" designation.
- Son of Sevenless (SOS) proteins facilitate Ras activation by catalyzing GDP/GTP exchange, a critical step in the Ras signaling pathway.
Purpose of the Study:
- To review recent advancements in designing small-molecule modulators and peptide mimetics targeting the Ras-SOS protein-protein interaction (PPI) interface.
- To explore strategies for overcoming potential drug resistance to Ras-SOS inhibitors.
Main Methods:
- Focus on small-molecule and peptide mimetic design targeting the Ras-SOS PPI.
- Review of accumulated data on inhibitors aimed at the Ras-SOS interface.
- Proposal of combination therapy strategies.
Main Results:
- The Ras-SOS PPI interface presents a viable target for therapeutic intervention in Ras-driven cancers.
- Small molecules and peptide mimetics show potential for modulating the Ras-SOS interaction.
- Drug resistance remains a significant challenge for targeted therapies.
Conclusions:
- Targeting the Ras-SOS PPI is a recognized strategy for developing novel cancer therapeutics.
- Combination therapies, termed "pathway drug cocktails," are proposed to combat drug resistance.
- A comprehensive classification of cancer types, cell/tissue contexts, and signaling pathways is needed to guide effective combination therapy development.
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