Phthalimide conjugation as a strategy for in vivo target protein degradation

TLDR

Certain oncogenic proteins are difficult to target therapeutically, prompting the development of novel degradation strategies. The authors devised a chemical strategy that attaches a protein‑binding ligand to a molecule that recruits an enzyme directing the target protein to the cell’s degradation machinery. In a proof‑of‑concept study, selective degradation of the transcriptional coactivator BRD4 delayed leukemia progression in mice. Winter et al., Science, p.

Abstract

A degrading game plan for cancer therapy Certain classes of proteins that contribute to cancer development are challenging to target therapeutically. Winter et al. devised a chemical strategy that, in principle, permits the selective degradation of any protein of interest. The strategy involves chemically attaching a ligand known to bind the desired protein to another molecule that hijacks an enzyme whose function is to direct proteins to the cell's protein degradation machinery. In a proof-of-concept study, they demonstrated selective degradation of a transcriptional coactivator called bromodomain-containing protein 4 and delayed the progression of leukemia in mice. Science , this issue p. 1376