Photocleavable Dimerizer for the Rapid Reversal of Molecular Trap Antagonists

Herein, we report the development of a photocleavable analog of AP20187, a cell-permeable molecule used to dimerize FK506-binding protein (FKBP) fusion proteins and initiate biological signaling cascades and gene expression or disrupt protein-protein interactions. We demonstrate that this reagent permits the unique ability to rapidly and specifically antagonize a molecular interaction in vitro and follow a biological process due to this acute antagonism (e.g. endosome dispersion) and to release the trap upon photocleavage to follow the cell''s return to homeostasis. In addition, this photocleavable AP20187 analog can be used in other systems where the dimerization of FKBP has been used to initiate signaling pathways, offering the ability to correlate the duration of a signaling event and a cellular response.