Journal
CELL CHEMICAL BIOLOGY
Volume 25, Issue 11, Pages 1327-+Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2018.07.009
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Funding
- Cancer Research Society (Canada) [14014]
- Canadian Cancer Society Research Institute [703209]
- Princess Margaret Cancer Foundation (PMCF)
- Canadian Institutes of Health Research
- Connaught Fund
- Canada Foundation for Innovation
- PMCF
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KRAS is frequently mutated in several of the most lethal types of cancer; however, the KRAS protein has proven a challenging drug target. K-RAS4B must be localized to the plasma membrane by prenylation to activate oncogenic signaling, thus we endeavored to target the protein-membrane interface with small-molecule compounds. While all reported lead compounds have low affinity for KRAS in solution, the potency of Cmpd2 was strongly enhanced when prenylated K-RAS4B is associated with a lipid bilayer. We have elucidated a unique mechanism of action of Cmpd2, which simultaneously engages a shallow pocket on KRAS and associates with the lipid bilayer, thereby stabilizing KRAS in an orientation in which the membrane occludes its effector-binding site, reducing RAF binding and impairing activation of RAF. Furthermore, enrichment of Cmpd2 on the bilayer enhances potency by promoting interaction with KRAS. This insight reveals a novel approach to developing inhibitors of membrane-associated proteins.
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