Heterobifunctional molecules have proven powerful tools to induce ligase-dependent ubiquitination, and subsequent degradation, of target proteins.  Conceivably, a similar strategy could be utilized to affect change in many other types of posttranslational modifications (PTMs) beyond ubiquitin.  We describe here a novel chemical strategy for controlling posttranslational phosphorylation.  Heterobifunctional molecules were designed to promote the proximity of a protein phosphatase (PP1) to protein targets.  The synthesized molecules induced the PP1-dependent dephosphorylation of AKT and EGFR.  To our knowledge, this work represented the first examples of small molecules recruiting non-native partners to induce removal of a PTM.

Phosphatase recruiting chimeras (PhoRCs) promote dephosphorylation of AKT and EGFR

ACS Spring 2022

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