Figure 1.

In this Perspective, the chemical biology toolsets built upon proximity enhancement are classified into two general categories, Class I and Class II. Class I is further broken into two subclasses: in Subclass Ia, the bifunctional probe enables recruitment of two or more distinct biological entities (proteins/cells), thereby promoting a response; and in Subclass Ib, one pole of the small molecule serves as an anchor to the POI and the other pole reacts intramolecularly with the same POI. In Class II, on-demand precision targeting enables the reactive entity to be unmasked in situ and targeted to (or the microenvironment of) POI. In all cases, in the absence of ligands known to bind POI, ligands generic to various protein- and peptide-based tags (Halo, CLIP, SNAP, PRIME, etc.) that can be fused to POIs may be integrated into the probes.