PTGR1 (Prostaglandin Reductase 1, bioactivating enzyme)

Class

Acylfulvene-derived DNA-damaging prodrug (PTGR1-activated alkylator)

Pathway

PTGR1 converts the prodrug into a reactive metabolite causing DNA interstrand crosslinks/double-strand breaks, selectively lethal in DDR-deficient, PTGR1-overexpressing tumors

PTGR1 (prostaglandin reductase 1) is a cytosolic enzyme best known for metabolizing certain prostaglandin derivatives, but it can also convert a class of prodrugs called acylfulvenes into reactive, DNA-damaging alkylating agents. This mechanism exploits a difference in enzyme expression between tumor and normal tissue: many cancers express higher levels of PTGR1 than surrounding healthy tissue, so an inert prodrug given systemically is preferentially transformed into its active, cytotoxic form inside tumor cells. The activated metabolite creates DNA interstrand crosslinks and double-strand breaks, lesions that block DNA replication and transcription. Tumor cells that also carry defects in DNA damage response (DDR) pathways, such as impaired nucleotide excision repair or homologous recombination, are especially unable to resolve this damage, leading to selective cell death. The pairing of an activating enzyme with a repair-deficiency vulnerability is the biological rationale for this strategy, aiming to widen the therapeutic window relative to conventional DNA-damaging chemotherapy that affects healthy dividing cells indiscriminately. Such a mechanism is broadly relevant across solid tumors where PTGR1 overexpression and DDR deficiency co-occur, offering a route toward selectively targeting cancer cells while sparing tissue with lower enzyme activity.