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
  • 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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