Cell-Based Kinetic Target-Guided Synthesis of an Enzyme Inhibitor

Finding a new drug
candidate for a selected target is an expensive
and time-consuming process. Target guided-synthesis, or in
situ click chemistry, is a concept where the drug target
is used to template the formation of its own inhibitors from reactive
building blocks. This could simplify the identification of drug candidates.
However, with the exception of one example of an RNA-target, target-guided
synthesis has always employed purified targets. This limits the number
of targets that can be screened by the method. By applying methods
from the field of metabolomics, we demonstrate that target-guided
synthesis with protein targets also can be performed directly in cell-based
systems. These methods offer new possibilities to conduct screening
for drug candidates of difficult protein targets in cellular environments.