A Comprehensive Review of Marketed KRAS Inhibitors and Degraders: Challenges and Opportunities

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The rat sarcoma virus oncogene (RAS) is a frequent driver in human cancers.
• Targeting RAS proteins is challenging due to their complex structure.
• Drug resistance limits the efficacy of current Kirsten RAS (KRAS) inhibitors.

Purpose of the Study:

• To review the structural basis and signaling networks of KRAS.
• To discuss recent advancements in KRAS inhibitor research.
• To explore proteolysis-targeting chimeras (PROTACs) as a strategy to overcome KRAS inhibitor resistance.

Main Methods:

• Literature review of KRAS structure and signaling.
• Analysis of recent developments in KRAS inhibitor therapies.
• Examination of PROTAC technology for mutant KRAS degradation.

Main Results:

• Covalent KRAS inhibitors represent a milestone in targeting mutant KRAS.
• PROTACs offer a novel approach to degrade mutant KRAS proteins.
• Understanding KRAS structure is crucial for developing effective therapies.

Conclusions:

• PROTACs present a promising strategy to overcome drug resistance in KRAS-mutated cancers.
• Further research into KRAS inhibitors and PROTACs can expand therapeutic options.
• This review provides a foundation for future KRAS-targeted therapy development.