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Inhibition of K-RAS4B by a Unique Mechanism of Action: Stabilizing Membrane-Dependent Occlusion of the Effector-Binding Site.

  • Fang Z Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
  • Marshall CB Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada. Electronic address: cmarshal@uhnresearch.ca.
  • Nishikawa T Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
  • Gossert AD Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Basel 4002, Switzerland; Institute for Molecular Biology and Biophysics, Department of Biology, ETH Zürich, Zürich 8093, Switzerland.
  • Jansen JM Department of Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Emeryville, CA 94608, USA.
  • Jahnke W Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Basel 4002, Switzerland.
  • Ikura M Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada. Electronic address: mikura@uhnresearch.ca.
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  • 2018-08-21
Published in:
  • Cell chemical biology. - 2018
HADDOCK
KRAS
NMR
cancer
drug discovery
membrane-associated protein
nanodisc
paramagnetic relaxation enhancement
phospholipid bilayer
prenylation
Animals
Antineoplastic Agents
Drug Discovery
Enzyme Inhibitors
Humans
Indoles
Lipid Bilayers
Models, Molecular
Piperidines
Proto-Oncogene Proteins p21(ras)
English 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.
Language
  • English
Open access status
bronze
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Persistent URL
https://sonar.ch/global/documents/52443
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