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 <b>6e</b> was administered to healthy rats and demonstrated high oral bioavailability, along with a long <i>in vivo</i> 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.
Authors
- Nicolò Filippi (ORCID: https://orcid.org/0000-0002-1200-9753)
- Ingrid De Meester (ORCID: https://orcid.org/0000-0002-3421-0124)
- Koen Augustyns (ORCID: https://orcid.org/0000-0002-5203-4339)
- Emile Verhulst (ORCID: https://orcid.org/0000-0002-8798-2750)
- Dominique Schols (ORCID: https://orcid.org/0000-0003-3256-5850)
- Pim‐Bart Feijens (ORCID: https://orcid.org/0000-0001-9510-3501)
- Vanesa Nozal (ORCID: https://orcid.org/0000-0001-5260-5683)
- R. Hermans (ORCID: https://orcid.org/0000-0001-7670-1944)
- Margarida Espadinha (ORCID: https://orcid.org/0000-0002-7053-0475)
- Pieter Van der Veken (ORCID: https://orcid.org/0000-0003-1208-3571)
- Guy Caljon (ORCID: https://orcid.org/0000-0002-4870-3202)
- Sarah G.J.A. Peeters (ORCID: https://orcid.org/0000-0002-9313-7027)
- Tiphanie Gomard
- Laura Dirkx (ORCID: https://orcid.org/0000-0002-1020-466X)
- Siham Benramdane (ORCID: https://orcid.org/0000-0001-5874-553X)
- Joni De Loose (ORCID: https://orcid.org/0000-0002-1536-3045)
- Sam Corthaut (ORCID: https://orcid.org/0000-0001-7526-3196)
- K. Mertens (ORCID: https://orcid.org/0000-0002-5845-0069)
Institutions
- University of Antwerp (BE)
- Rega Institute for Medical Research (BE)
- de Duve Institute (BE)
- UCLouvain (BE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-10-29
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02049
- Primary Topic
- Peptidase Inhibition and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 0.00