Profiling Diverse Chemical Space to Map the Druggable Proteome

Chemoproteomics is a powerful mass spectrometry?based affinity chromatography approach for identifying proteome-wide small molecule-protein interactions.1 It aims for unbiased determination of drug targets in a complex cellular environment. Chemoproteomics has been one of the central methods of choice for small molecule mechanism of action (MOA) deconvolution of phenotypic screen hits, as well as for understanding the selectivity and off-target biological activities. In order to understand the modulation of the human proteome with small molecules in a comprehensive and systematic manner, a chemically diverse probe set with drug-like characteristics has been selected and profiled against 8 relevant biosamples including cells and human organ tissues to delineate protein target binding spectra in an unbiased manner at a global scale. In this work, we will update progress-to-date on experimental design, optimization, and current findings from this unprecedented rich system-chemical biology dataset. We will use examples from this study to highlight the cheminformatics and bioinformatics solutions that we developed to address the unique challenge of chemical biology/chemical proteomics data. Insights from this chemoproteomics profiling effort will be discussed from the perspectives of: 1) compound selectivity in the context of diverse biological samples beyond industry standard practice of using in vitro recombinant protein profiling panel or in one or two model cell lines, 2) frequent targets and chemo type hitters as well as 3) novel potential target examples. These efforts to develop a unique human chemo-proteomic database, together with chemo-genomic and transcriptomic approaches, provide chemical biologists the means to prosecute novel target identification and subsequent validation studies in support of relevant disease areas.