Protein Degradation by In-Cell Self-Assembly of Proteolysis Targeting Chimeras.

ABSTRACT: Selective degradation of proteins by proteolysis targeting chimeras (PROTACs) offers a promising potential alternative to protein inhibition for therapeutic intervention. Current PROTAC molecules incorporate a ligand for the target protein, a linker, and an E3 ubiquitin ligase recruiting group, which bring together target protein and ubiquitinating machinery. Such hetero-bifunctional molecules require significant linker optimization and possess high molecular weight, which can limit cellular permeation, solubility, and other drug-like properties. We show here that the hetero-bifunctional molecule can be formed intracellularly by bio-orthogonal click combination of two smaller precursors. We designed a tetrazine tagged thalidomide derivative which reacts rapidly with a trans-cyclo-oc

SUBMITTER: Lebraud H 

PROVIDER: S-EPMC5200928 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature