Fragment-Sized Thiazoles in Fragment-Based Drug Discovery Campaigns: Friend or Foe?

Thiazoles exhibit a wide range of biological activities
and therefore
represent useful and attractive building blocks. To evaluate their
usefulness and pinpoint their liabilities in fragment screening campaigns,
we assembled a focused library of 49 fragment-sized thiazoles and
thiadiazoles with various substituents, namely amines, bromides, carboxylic
acids, and nitriles. The library was profiled in a cascade of biochemical
inhibition assays, redox activity, thiol reactivity, and stability
assays. Our study indicates that when thiazole derivatives are identified
as screening hits, their reactivity should be carefully addressed
and correlated with specific on-target engagement. Importantly, nonspecific
inhibition should be excluded using experimental approaches and in silico predictions. To help with validation of hits identified
in fragment screening campaigns, we can apply our high-throughput
profiling workflow to focus on the most tractable compounds with a
clear mechanism of action.