Biochemistry
Biochemistry
5 years ago

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

Design of Small Molecules That Compete with Nucleotide Binding to an Engineered Oncogenic KRAS Allele
Brent R. Stockwell, Marie-Hélène Larraufie, Lewis M. Brown, Hemanth Akkiraju, Leila Musavi, Yan Zhang
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.

Publisher URL: http://dx.doi.org/10.1021/acs.biochem.7b01113

DOI: 10.1021/acs.biochem.7b01113

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