Eliminating oncogenic RAS: back to the future at the drawing board.

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• RAS proteins are key oncogenes driving cancer, with recent progress in developing direct KRAS inhibitors.
• Resistance to targeted therapies, including covalent KRAS-G12C inhibitors, is a significant clinical challenge.
• RAS proteins were historically considered undruggable due to a lack of accessible binding pockets.

Purpose of the Study:

• To review novel approaches for targeting four druggable sites on RAS proteins.
• To analyze lessons learned from developing covalent and non-covalent RAS inhibitors.
• To explore the potential of macromolecular binders and small molecule binders for future RAS-targeted therapies.

Main Methods:

• Review of scientific literature on RAS drug development, focusing on covalent and non-covalent inhibitors.
• Analysis of strategies utilizing macromolecular binders for target site discovery and validation.
• Exploration of future directions including small molecule binders and novel targeting modalities like degraders.

Main Results:

• Development of allele-specific covalent and non-covalent RAS inhibitors has provided valuable insights.
• Macromolecular binders show potential for identifying and validating new druggable sites on RAS.
• Small molecule binders are emerging as a promising avenue, potentially leading to improved inhibitors and degraders.

Conclusions:

• Novel strategies are crucial for overcoming resistance and effectively targeting RAS oncogenes.
• Reversible small molecule binders could enable targeted RAS degradation, potentially reducing on-target toxicity.
• Continued innovation in small molecule design is essential for treating RAS-driven cancers and RASopathies.