Photocontrolled trimethoprim PROTACs targeting the eDHFR protein tag.

ABSTRACT: Proteolysis targeting chimeric small molecules (PROTACs) offer a strategy for degrading disease-associated proteins or controlling engineered protein tags fused to therapeutic proteins, like chimeric antigen receptors (CARs). New approaches are needed that allow spatiotemporal control of PROTAC activity, restricting degrader activity to targeted cells. Photopharmacology offers a solution by enabling light-mediated spatial control of drug action. Here, we synthesize photocaged and photoswitchable PROTAC molecules and test their regulation of proteins tagged with E. coli dihydrofolate reductase (eDHFR) in tumor and CAR-T cells. Several of the molecules are derived from triazole-linked trimethoprim-PROTACs (TMP-TACtz), that degrade eDHFR fused proteins at picomolar concentrations, show degrad

SUBMITTER: Sharma N 

PROVIDER: S-EPMC12824167 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature