期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 23, 页码 14404-14424出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c01312
关键词
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资金
- National Natural Science Foundation of China [81922062]
- National Key Research and Development Program of China [2018YFE0105800]
- Guangdong Provincial Science and Technology Program, Jinan University [2018A050506043]
- Health Research Council of New Zealand [18/1016]
- Cancer Society Auckland Northland
KRAS, the most frequently mutated oncogene, plays a predominant role in driving initiation and progression of cancers. Decades of effort to target KRAS using small molecules has been unsuccessful, causing KRAS to be considered an undruggable cancer target. However, this view began to change recently, as drug discovery techniques have developed several KRAS G12C allosteric inhibitors that are currently being evaluated in clinical trials. Herein we provide an in-depth analysis of the structure and binding pockets of KRAS, medicinal chemistry optimization processes, and the biological characterization of small-molecule inhibitors that directly target KRAS, including covalent allosteric inhibitors specific for the G12C mutant, GTP-competitive inhibitors targeting the nucleotide-binding site, and protein-protein interaction inhibitors that bind in the switch I/II pocket or the A59 site. Additionally, we propose potential challenges faced by these new classes of KRAS inhibitors under clinical evaluation.
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