ABSTRACT: Kinetic target-guided synthesis (KTGS) is a powerful screening approach that enables identification of small molecule
modulators for biomolecules. While many KTGS variants have emerged, a majority of the examples suffer from limited throughput
and a poor signal/noise ratio, hampering reliable hit detection. Herein, we present our optimized multifragment KTGS screening
strategy that tackles these limitations. This approach utilizes selected reaction monitoring liquid chromatography tandem mass
spectrometry for hit detection, enabling the incubation of 190 fragment combinations per screening well. Consequentially, our
fragment library was expanded from 81 possible combinations to 1710, representing the largest KTGS screening library assembled to
date. The expanded library was screened against Mcl-1, leading to the discovery of 24 inhibitors. This work unveils the true potential
of KTGS with respect to the rapid and reliable identification of hits, further highlighting its utility as a complement to the existing
repertoire of screening methods used in drug discovery.
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Markus Queisser
Scientific Director
GlaxoSmithKline
Stevenage
441438764034
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