KRasG12C inhibitors in clinical trials: a short historical perspective

KRas is the most frequently mutated oncogene in human cancer, and even 40 years after the initial discovery of Ras oncogenes in 1982, no approved drug directly targets Ras in Ras-driven cancer. New information and approaches for direct targeting of mutant Ras have fueled hope for the development of...

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Bibliographic Details
Published in:MedChemComm 2020-07, Vol.11 (7), p.76-77
Main Authors: Goebel, Lisa, Müller, Matthias P, Goody, Roger S, Rauh, Daniel
Format: Article
Language:English
Subjects:
Cancer
Clinical trials
Guanosine diphosphate
Inhibitors
Ras protein
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Summary:KRas is the most frequently mutated oncogene in human cancer, and even 40 years after the initial discovery of Ras oncogenes in 1982, no approved drug directly targets Ras in Ras-driven cancer. New information and approaches for direct targeting of mutant Ras have fueled hope for the development of direct KRas inhibitors. In this review, we provide a comprehensive historical perspective of the development of promising KRasG12C inhibitors that covalently bind to the mutated cysteine residue in the switch-II pocket and trap the protein in the inactive GDP bound state. After decades of failure, three covalent G12C-specific inhibitors from three independent companies have recently entered clinical trials and therefore represent new hope for patients suffering from KRasG12C driven cancer. Short historical perspective of the development of promising KRasG12C inhibitors that have recently entered clinical trials.
ISSN:2632-8682
2040-2503
2632-8682
2040-2511
DOI:10.1039/d0md00096e