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Novel K-Ras G12C Switch-II Covalent Binders Destabilize Ras and Accelerate Nucleotide Exchange.


ABSTRACT: The success of targeted covalent inhibitors in the global pharmaceutical industry has led to a resurgence of covalent drug discovery. However, covalent inhibitor design for flexible binding sites remains a difficult task due to a lack of methodological development. Here, we compared covalent docking to empirical electrophile screening against the highly dynamic target K-RasG12C. While the overall hit rate of both methods was comparable, we were able to rapidly progress a docking hit to a potent irreversible covalent binder that modifies the inactive, GDP-bound state of K-RasG12C. Hydrogen-deuterium exchange mass spectrometry was used to probe the protein dynamics of compound binding to the switch-II pocket and subsequent destabilization of the nucleotide-binding region. SOS-mediated nucleotide exchange assays showed that, contrary to prior switch-II pocket inhibitors, these new compounds appear to accelerate nucleotide exchange. This study highlights the efficiency of covalent docking as a tool for the discovery of chemically novel hits against challenging targets.

SUBMITTER: Nnadi CI 

PROVIDER: S-EPMC6179444 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Novel K-Ras G12C Switch-II Covalent Binders Destabilize Ras and Accelerate Nucleotide Exchange.

Nnadi Chimno I CI   Jenkins Meredith L ML   Gentile Daniel R DR   Bateman Leslie A LA   Zaidman Daniel D   Balius Trent E TE   Nomura Daniel K DK   Burke John E JE   Shokat Kevan M KM   London Nir N  

Journal of chemical information and modeling 20180131 2


The success of targeted covalent inhibitors in the global pharmaceutical industry has led to a resurgence of covalent drug discovery. However, covalent inhibitor design for flexible binding sites remains a difficult task due to a lack of methodological development. Here, we compared covalent docking to empirical electrophile screening against the highly dynamic target K-Ras<sup>G12C</sup>. While the overall hit rate of both methods was comparable, we were able to rapidly progress a docking hit t  ...[more]

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