The KRASG12C protein product is an attractive, yet challenging, target for small molecule inhibition.<b>  </b>One option for therapeutic intervention is to design small molecule ligands capable of binding to, and inactivating KRASG12C, via formation of a covalent bond to the sulfhydryl group of cysteine 12.   In order to better understand the cellular off-target interactions of a covalent KRASG12C inhibitor, we have completed a series of complimentary chemical proteomics experiments in H358 cells.  A new thiol reactive activity based proteomic profiling (ABPP) probe was designed and used to construct a cellular target occupancy assay for KRASG12C.  In addition, the ABPP probes allowed us to profile potential off target interactions of covalent KRASG12C inhibitor with over 3200 cysteine residues.  In order to complement the ABPP data we designed an alkyne containing covalent probe, to serve as bait in competitive chemical proteomics experiments.    Herein, we describe and compare data from both the ABPP, and the click chemistry probe pull down experiments.

Chemical proteomic characterization of a covalent KRAS G12C inhibitor

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.