biostudies-literatureSharma NCancer Research Institute (CRI)U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)NIGMS NIH HHSNIH HHSU.S. Department of Health & Human Services | NIH | NIH Office of the Director (OD)822https://www.ebi.ac.uk/biostudies/studies/S-EPMC12824167biostudies-literatureUnknown17(1)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 degradNature communicationsPhotocontrolled trimethoprim PROTACs targeting the eDHFR protein tag.PMC12824167R01 GM150804DP5-OD26386R01GM126228CRI5589DP5 OD026386R01GM150804R01 GM126228Sharma NFlores JSarkar STrauner DNguyen TGong AZEdwards KJKo TSellmyer MAPham JMfalsePhotocontrolled trimethoprim PROTACs targeting the eDHFR protein tag.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 degrad2025-01-01T00:00:00Z2025 Dec2026-06-06T21:49:02.544Z2026-06-05T03:11:20.991ZS-EPMC128241674145390410.1038/s41467-025-67527-5