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Biochemistry. 2018 Feb 27;57(8):1380-1389. doi: 10.1021/acs.biochem.7b01113. Epub 2018 Feb 6.

Design of Small Molecules That Compete with Nucleotide Binding to an Engineered Oncogenic KRAS Allele.

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Quantitative Proteomics and Metabolomics Center, Columbia University , New York, New York 10027, United States.


RAS mutations are found in 30% of all human cancers, with KRAS the most frequently mutated among the three RAS isoforms (KRAS, NRAS, and HRAS). However, directly targeting oncogenic KRAS with small molecules in the nucleotide-binding site has been difficult because of the high affinity of KRAS for GDP and GTP. We designed an engineered allele of KRAS and a covalent inhibitor that competes for GTP and GDP. This ligand-receptor combination demonstrates that the high affinity of GTP and GDP for RAS proteins can be overcome with a covalent inhibitor and a suitably engineered binding site. The covalent inhibitor irreversibly modifies the protein at the engineered nucleotide-binding site and is able to compete with GDP and GTP. This provides a new tool for studying KRAS function and suggests strategies for targeting the nucleotide-binding site of oncogenic RAS proteins.

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