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Eliminating oncogenic RAS: back to the future at the drawing board
Candy Laura Steffen1, Pelin Kaya1, Elisabeth Schaffner-Reckinger1
1Cancer Cell Biology and Drug Discovery Group, Department of Life Sciences and Medicine, University of Luxembourg, L-4362 Esch-sur-Alzette, Luxembourg.
Abstract:
RAS drug development has made enormous strides in the past ten years, with the first direct KRAS inhibitor being approved in 2021. However, despite the clinical success of covalent KRAS-G12C inhibitors, we are immediately confronted with resistances as commonly found with targeted drugs. Previously believed to be undruggable due to its lack of obvious druggable pockets, a couple of new approaches to hit this much feared oncogene have now been carved out. We here concisely review these approaches to directly target four druggable sites of RAS from various angles. Our analysis focuses on the lessons learnt during the development of allele-specific covalent and non-covalent RAS inhibitors, the potential of macromolecular binders to facilitate the discovery and validation of targetable sites on RAS and finally an outlook on a future that may engage more small molecule binders to become drugs. We foresee that the latter could happen mainly in two ways: First, non-covalent small molecule inhibitors may be derived from the development of covalent binders. Second, reversible small molecule binders could be utilized for novel targeting modalities, such as degraders of RAS. Provided that degraders eliminate RAS by recruiting differentially expressed E3-ligases, this approach could enable unprecedented tissue- or developmental stage-specific destruction of RAS with potential advantages for on-target toxicity. We conclude that novel creative ideas continue to be important to exterminate RAS in cancer and other RAS pathway-driven diseases, such as RASopathies.
Insights
Targeting RAS oncogenes, including KRAS, has advanced with new inhibitors. Despite resistance to current drugs, novel strategies like small molecule binders and degraders offer future promise for treating RAS-driven cancers and diseases.
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.
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