Filippi_2025_J.Med.Chem__

Dipeptidyl peptidase 9 (DPP9) is a key regulator of pyroptosis in leukocytes. DPP9-targeting inhibitors have been reported to selectively induce pyroptosis in human acute myeloid leukemia (AML) cells and work synergistically with non-nucleoside reverse transcriptase inhibitors (NNRTIs) to kill HIV-1-infected lymphocytes. Here, we report structure-activity relationship data for a novel series of low nanomolar DPP9 inhibitors with unprecedented pyroptosis-inducing potency and kinetics. They have substantial DPP9-to-DPP8 selectivity and full selectivity over other related peptidases, including DPP4. The selected compound 6e was administered to healthy rats and demonstrated high oral bioavailability, along with a long in vivo and microsomal half-life. Finally, we also investigated the pyroptosis induction potential in HIV-1-infected T-lymphocytes. These new compounds have the potential to become important research tools and support further progress in DPP9's therapeutic potential.