PhosTACs

Protein phosphorylation, which regulates many critical aspects of cell biology, is dynamically governed by kinases and phosphatases. Many diseases are associated with dysregulated hyperphosphorylation of critical proteins, such as retinoblastoma protein in cancer. Although kinase inhibitors have been widely applied in the clinic, growing evidence of off-target effects and increasing drug resistance prompts the need to develop a new generation of drugs. Here, we propose a proof-of-concept study of phosphorylation targeting chimeras (PhosTACs). Similar to PROTACs in their ability to induce ternary complexes, PhosTACs focus on recruiting a Ser/Thr phosphatase to a phosphosubstrate to mediate its dephosphorylation. However, distinct from PROTACs, PhosTACs can uniquely provide target gain-of-function opportunities to manipulate protein activity.
PhosTACs (Phosphatase-Targeting Chimeric Molecules) is a new approach different than non-discriminatorily activating phosphatase activity to effect widespread substrate dephosphorylation. PhosTACs uses heterobifunctional molecules to mediate complex formation between a phosphatase and a targeted phosphoprotein to affect focused, targeted dephosphorylation of the latter. This is an adaptation of our PROTAC technology, wherein bifunctional small molecules alter target protein ubiquitination to induce degradation^[1][2].