Multiplexed Target Profiling with Integrated Chemical Genomics and Chemical Proteomics

Target identification is crucial for elucidating the
mechanisms
of bioactive molecules in drug discovery. However, traditional methods
assess compounds individually, making it challenging to efficiently
examine multiple compounds in parallel, especially for structurally
diverse compounds. This study reports a novel strategy called chemical
genomics-facilitated chemical proteomics (CGCP) for multiplexing the
target identification of bioactive small molecules. CGCP correlates
compounds’ perturbation of global transcription, or chemical
genomic profiles, with their reactivity toward target proteins, enabling
simultaneous identification of targets. We demonstrated the utility
of CGCP by studying the targets of celastrol (Cel) and four other
electrophilic compounds with varying levels of similarity to Cel based
on their chemical genomic profiles. We identified multiple novel targets
and binding sites shared by the compounds in a single experiment.
CGCP enabled multiplexity and improved the efficiency of target identification
for structurally distinct compounds, indicating its potential to accelerate
drug discovery.