posted on 2021-11-15, 23:03authored byPo-Han Chen, Zhenyi Hu, Elvira An, Ifunanya Okeke, Sijin Zheng, Xuanmeng Luo, Angela Gong, Saul Jaime-Figueroa, Craig M. Crews
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. In this study, we applied a chemical biology approach
to evaluate the feasibility of PhosTACs by recruiting the scaffold
and catalytic subunits of the PP2A holoenzyme to protein substrates
such as PDCD4 and FOXO3a for targeted protein dephosphorylation. For
FOXO3a, this dephosphorylation resulted in the transcriptional activation
of a FOXO3a-responsive reporter gene.