Drug interaction mapping with proximity dependent enzyme recruiting chimeras

Abstract

Proximity dependent labeling using engineered enzymes has been used extensively to identify protein-protein interactions, and map protein complexes in-vitro and in-vivo. Here, we extend the use of engineered promiscuous biotin ligases to the identification of small molecule protein targets. Chimeric bi-functional chemical probes ("recruiters") are used to effectively recruit tagged biotin ligases for proximity dependent labeling of target and target interactors. The broad applicability of this approach is demonstrated with probes developed from a multi-kinase inhibitor, a bromodomain targeting moiety, and an FKBP targeting molecule. While complementary to traditional chemo-proteomic strategies such as photo-affinity labeling (PAL), and activity-based protein profiling (ABPP), this approach is a useful addition to the target ID toolbox with opportunities for tunability based on the inherent labeling efficiencies of different engineered enzymes and control over the enzyme cellular localization.