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Expanding the Scope of Electrophiles Capable of Targeting K‑Ras Oncogenes
There is growing interest in reversible
and irreversible covalent
inhibitors that target noncatalytic amino acids in target proteins.
With a goal of targeting oncogenic K-Ras variants (e.g., G12D) by
expanding the types of amino acids that can be targeted by covalent
inhibitors, we survey a set of electrophiles for their ability to
label carboxylates. We functionalized an optimized ligand for the
K-Ras switch II pocket with a set of electrophiles previously reported
to react with carboxylates and characterized the ability of these
compounds to react with model nucleophiles and oncogenic K-Ras proteins.
Here, we report that aziridines and stabilized diazo groups preferentially
react with free carboxylates over thiols. Although we did not identify
a warhead that potently labels K-Ras G12D, we were able to study the
interactions of many electrophiles with K-Ras, as most of the electrophiles
rapidly label K-Ras G12C. We characterized the resulting complexes
by crystallography, hydrogen/deuterium exchange, and differential
scanning fluorimetry. Our results both demonstrate the ability of
a noncatalytic cysteine to react with a diverse set of electrophiles
and emphasize the importance of proper spatial arrangements between
a covalent inhibitor and its intended nucleophile. We hope that these
results can expand the range of electrophiles and nucleophiles of
use in covalent protein modulation