Selective and Orally Bioavailable Dipeptidyl Peptidase 9 Inhibitors with Potent Pyroptosis Induction Properties

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.