Drugging the undruggable Ras: mission possible?

By A. Cox, Stephen W. Fesik, Alec C. Kimmelman, Ji Luo, C. Der. Nature reviews. Drug discovery, 2014

1,780 citations recorded by the source corpus.

Despite more than three decades of intensive effort, no effective pharmacological inhibitors of the RAS oncoproteins have reached the clinic, prompting the widely held perception that RAS proteins are 'undruggable'. However, recent data from the laboratory and the clinic have renewed our hope for the development of RAS-inhibitory molecules. In this Review, we summarize the progress and the promise of five key approaches. Firstly, we focus on the prospects of using direct inhibitors of RAS. Secondly, we address the issue of whether blocking RAS membrane association is a viable approach. Thirdly, we assess the status of targeting RAS downstream effector signalling, which is arguably the most favourable current approach. Fourthly, we address whether the search for synthetic lethal interactors of mutant RAS still holds promise. Finally, RAS-mediated changes in cell metabolism have recently been described and we discuss whether these changes could be exploited for new therapeutic directions. We conclude with perspectives on how additional complexities, which are not yet fully understood, may affect each of these approaches.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d1aa0a28d61d654d3807ca5226931a4848e10994

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In Molecular Biology

1. D. Tang
2. R. Kang
3. Guido Kroemer
4. H. J. Zeh
5. K. Rossman
6. C. Der
7. Xinxin Song
8. Doralicia Casares

Citations in the corpus

• Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations (2015, background): “Mol Cancer Res; 13(9) September 2015 Molecular Cancer Research 1330”
• The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity. (2017, positive): “Members of the small GTPase RAS family (K-RAS, H-RAS, and N-RAS) aremutated in one-third of all human cancers, thus representing an important target for anti-cancer drug development (Cox et al., 2014).”
• RAS isoforms and mutations in cancer at a glance (2016, background): “For example, there is near-exclusive mutation of KRAS in pancreatic ductal, lung and colorectal carcinoma, whereas NRAS is the predominant isoform mutated in cutaneous melanoma (Cox et al., 2014).”
• Membrane Lipid Composition: Effect on Membrane and Organelle Structure, Function and Compartmentalization and Therapeutic Avenues (2019, background): “Thus, MLT is a sophisticated therapeutic approach to make protein–protein interactions targetable in an environment where those interactions are not amenable to manipulation [139,205,206].”
• Recent advances in the development of protein–protein interactions modulators: mechanisms and clinical trials (2020, background): “Specially, the KRAS mutation has been observed in a large proportion of pancreatic cancers.(133) The RAS mutations lead the cells on the hyperactive state for unlimited proliferation.”