Chemoproteomics applications for target deconvolution, mapping of druggable pockets and exploration of novel modalities

Quantitative chemoproteomics approaches, such as the combination of small molecule affinity chromatography or photo-affinity labeling with mass spectrometry-based protein identification and quantitation, are key tools for target deconvolution for non-covalent and covalent bioactive compounds such as hits from phenotypic screens. For covalent compounds and probes, in addition to providing information about the cellular protein interactome of a compound of interest, chemoproteomics workflows also provide more granular information about the specific modified amino acid. This allows the mapping of solvent-exposed druggable pockets in a forward-looking manner, ligands for which will be either functional modulators or silent binders for which the binding event does not lead to a functional consequence. However, the recent rise of chemically induced proximity-based approaches using heterobifunctional molecules as exemplified by targeted protein degradation (TPD) has enabled the functionalization of such silent binders and thus further increased the interest in proteome-wide ligandibility studies using chemoproteomics approaches. For TPD, such a heterobifunctional molecule consists of a E3 ubiquitin ligase-recruitment module linked to a ligand for the target of interest with the resulting recruitment event leading to ubiquitination and subsequent degradation of the protein of interest. In addition to E3 ligases, an increasing number of active enzyme classes, including DUBs, kinases and phosphatases, have been successfully recruited for target modification and modulation using suitable modules for recruitment of the active form of the enzyme. These chemical biology efforts are quickly increasing our repertoire of modalities for therapeutic intervention in disease. Applications of chemoproteomics in the various contexts mentioned above will be presented and discussed.