Progress in RAS-targeted therapeutic strategies: From small molecule inhibitors to proteolysis targeting chimeras

Area of Science:

• Oncology
• Chemical Biology
• Pharmacology

Background:

• Rat sarcoma (RAS) gene mutations are key drivers in multiple fatal cancers.
• Acquired drug resistance limits the clinical efficacy of current RAS subtype-specific inhibitors.

Purpose of the Study:

• To review current advances in RAS inhibitors.
• To focus on Proteolysis Targeting Chimeras (PROTACs) as a strategy against RAS mutations and drug resistance.

Main Methods:

• Literature review of RAS inhibitors.
• Exploration of PROTAC technology for targeting RAS mutations.
• Analysis of PROTACs' potential in overcoming drug resistance.

Main Results:

• PROTACs demonstrate significant therapeutic potential for "undruggable" targets.
• PROTACs offer a unique mechanism to combat acquired drug resistance in RAS-mutated cancers.
• PROTACs are a promising strategy to overcome the limitations of classical RAS inhibitors.

Conclusions:

• PROTACs represent a feasible strategy to address the bottleneck of classical RAS inhibitors.
• Targeting RAS mutations and downstream effectors with PROTACs holds promise for cancer treatment.
• Further research into PROTACs is crucial for developing effective therapies against RAS-driven cancers.