A Chemical Genetic Approach
for Covalent Inhibition
of Analogue-Sensitive Aurora Kinase
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Abstract
The perturbation of protein kinases with small organic
molecules
is a powerful approach to dissect kinase function in complex biological
systems. Covalent kinase inhibitors that target thiols in the ATP
binding pocket of the kinase domain proved to be ideal reagents for
the investigation of highly dynamic cellular processes. However, due
to the covalent inhibitors' possible off-target reactivities, it is
required that the overall shape of the inhibitor as well as the intrinsic
reactivity of the electrophile are precisely tuned to favor the reaction
with only the desired cysteine. Here we report on the design and biological
characterization of covalent anilinoquinazolines as potent inhibitors
of genetically engineered Aurora kinase in fission yeast