Abstract
Dipeptidyl-peptidase 9 (DPP9) is a post-proline cleaving serine protease. Lately, the enzyme captured the attention of immunology and oncology researchers, after it was shown that DPP9 inhibition causes pyroptosis (pro-inflammatory cell death), selectively in myeloid leukemia cells. To date, no selective DPP9 inhibitors have been reported. However, in early 2023 the host lab discovered a series of subnanomolar DPP9 inhibitors with selectivity indices > 103 against all other proline-selective proteases (unpublished data). These molecules will be structurally optimized and investigated toward three specific applications: 1) Inhibitors with maximal pyroptosis induction potency. Structural parameters will be investigated that maximally disrupt the protein-protein interaction (PPI) between DPP9 and the inflammasome sensors NLRP1 and CARD8. Disruption of these PPIs sets off pyroptosis induction. 2) Selective activity-based probes for DPP9. Proof-of-concept for these molecules will also be delivered by tracking active DPP9 inside live cells and quantifying it in cell lysate. 3) Inhibitors with optimized in vivo pharmacokinetics. This will maximize the impact and clinical translatability of our endeavors. Optimal molecules can become drug candidates, for example against myeloid leukemias.
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