2. Academic Validation
  3. Selective and Orally Bioavailable Dipeptidyl Peptidase 9 Inhibitors with Potent Pyroptosis Induction Properties

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

  • J Med Chem. 2025 Oct 29. doi: 10.1021/acs.jmedchem.5c02049.
Nicolò Filippi 1,  Kathleen Mertens 2,  Joni De Loose 2,  Siham Benramdane 1,  Robin Hermans 3,  Margarida Espadinha 1,  Laura Dirkx 4,  Pim-Bart Feijens 4,  Vanesa Nozal 1,  Emile Verhulst 2,  Sarah Peeters 1,  Tiphanie Gomard 5,  Sam Corthaut 2,  Koen Augustyns 1 6,  Guy Caljon 4 6,  Dominique Schols 3,  Ingrid De Meester 2 6,  Pieter Van der Veken 1 6
Affiliations

Affiliations

  • 1 Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, Wilrijk 2610, Belgium.
  • 2 Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, Wilrijk 2610, Belgium.
  • 3 Molecular, Structural and Translational Research group, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Herestraat 49, Leuven 3000, Belgium.
  • 4 Laboratory of Microbiology, Parasitology and Hygiene, Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, Wilrijkcity 2610, Belgium.
  • 5 Institut de Duve, Université Catholique de Louvain, Brussels 1200, Belgium.
  • 6 Infla-Med Centre of Excellence, University of Antwerp, Universiteitsplein 1, Wilrijk 2610, Belgium.
PMID: 41160575 DOI: 10.1021/acs.jmedchem.5c02049
Abstract

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.

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