Work

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

Year: 2018

Type: article

Abstract: 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.

Source: Biochemistry

DOI: 10.1021/acs.biochem.7b01113

Authors: Yan Zhang, Marie-Hélène Larraufie, Leila Musavi, Hemanth Akkiraju, Lewis M. Brown, Brent R. Stockwell

Institution: Columbia University

Language: English

Topic: Protein Kinase Regulation and GTPase Signaling

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green

Funders: National Institutes of Health, National Cancer Institute

Awards: Defining the functions and translational potential of ferroptosis, Roles and Regulation of wild-type and mutant forms of p53, Discovery of allele-selective KRAS inhibitors