How chemoproteomics can enable drug discovery and development

Abstract

Creating first-in-class medications to treat human disease is an extremely challenging endeavor. While genome sequencing and genetics are making direct connections between mutations and human disorders at an unprecedented rate, matching molecular targets with a suitable therapeutic indication must ultimately be achieved by pharmacology. Here, we discuss how the integration of chemical proteomic platforms (such as activity-based protein profiling) into the earliest stages of the drug discovery process has the potential to greatly expand the scope of proteins that can be pharmacologically evaluated in living systems, and, through doing so, promote the identification and prioritization of new therapeutic targets.

Figure 1

The metabolic serine hydrolases as a case study for the druggable, but not-yet-drugged proteome. (A) Tree diagram showing the ~115 human metabolic serine hydrolases. Enzymes possessing proof-of-relevance chemical probes developed prior to the application of ABPP to serine hydrolases are marked with red arrows. Enzymes with proof-of-relevance probes discovered with ABPP platforms are marked with blue arrows. (B) Chart displaying metabolic serine hydrolases as a function of number of scientific publications, where enzymes possessing proof-of-relevance chemical probes developed prior to or with the use of ABPP are marked in red and blue, respectively. Blue arrows are used to mark poorly characterized enzymes with low publication number for which ABPP has generated proof-of-relevance probes.

Figure 2

Representative chemoproteomic platforms for drug discovery and development. (A) Competitive ABPP for high-throughput screening of small-molecule libraries using fluorescence polarization (fluopol) for hit discovery and gel-based selectivity profiling in proteomes for hit prioritization. (B) SILAC-ABPP for quantitative assessment of inhibitor selectivity in proteomes. (C) Affinity enrichment combined with SILAC to quantify small-molecule-interacting proteins from native proteomes.

Figure 3

How chemoproteomics can enable drug discovery and development from the earliest stages of target and lead compound discovery through lead optimization and biomarker assays in preclinical and clinical development.