Abstract：
: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.
journal_name
Cell Chem Bioljournal_title
Cell chemical biologyauthors
Fang Z,Marshall CB,Nishikawa T,Gossert AD,Jansen JM,Jahnke W,Ikura Mdoi
10.1016/j.chembiol.2018.07.009subject
Has Abstractpub_date
2018-11-15 00:00:00pages
1327-1336.e4issue
11eissn
2451-9456issn
2451-9448pii
S2451-9456(18)30261-7journal_volume
25pub_type
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journal_title：Cell chemical biology
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journal_title：Cell chemical biology
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journal_title：Cell chemical biology
pub_type： 杂志文章
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pub_type： 杂志文章
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