Selective induction of PYROptosis in acute myeloid leukemia cells with VECTORized DPP9 inhibitors

Projektinformationen

PyroVector

ID Finanzhilfevereinbarung: 101155555

DOI

10.3030/101155555

Projekt abgeschlossen

EK-Unterschriftsdatum 8 März 2024

Startdatum 1 Mai 2024

Enddatum 30 April 2026

Finanziert unter

• Marie Skłodowska-Curie Actions (MSCA)

Gesamtkosten

Keine Daten

EU-Beitrag

€ 191 760,00

Koordiniert durch

UNIVERSITEIT ANTWERPEN
Belgium

Periodic Reporting for period 1 - PyroVector (Selective induction of PYROptosis in acute myeloid leukemia cells with VECTORized DPP9 inhibitors)

Berichtszeitraum: 2024-05-01 bis 2026-04-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Acute myeloid leukemia (AML) is an aggressive blood cancer associated with poor prognosis and frequent relapses despite significant advances in chemotherapy and targeted therapies. Current treatment options are often accompanied by substantial toxicity and many patients eventually develop resistance or experience disease recurrence. Therefore, the development of more selective therapeutic approaches remains an important unmet medical need.
Recent discoveries have identified dipeptidyl peptidase 9 (DPP9) as a promising therapeutic target in AML. Inhibition of DPP9 can trigger pyroptosis, a highly inflammatory form of programmed cell death. This unique mechanism creates exciting opportunities for the development of novel anti-cancer therapies. However, systemic administration of DPP9-targeting agents may also affect healthy tissues, highlighting the need for selective delivery strategies.
The PyroVector project aimed to address this challenge by developing vectorized DPP9-targeting molecules capable of selectively delivering pyroptosis-inducing agents to AML cells while minimizing off-target effects. Several delivery strategies were investigated, including antibody-drug conjugates, cell-penetrating peptides and small-molecule targeting ligands. In parallel, the project explored both inhibition- and degradation-based approaches to better understand how different mechanisms of target engagement influence biological responses.
By combining medicinal chemistry, targeted drug delivery and chemical biology, the project aimed to establish new strategies for selective induction of pyroptosis in leukemia cells and contribute to the development of safer and more effective therapies for hematological malignancies.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

During the fellowship, an extensive medicinal chemistry campaign resulted in the synthesis and characterization of a broad panel of DPP9-targeting molecules, including inhibitors, PROTACs, vectorized inhibitors and delivery platforms designed for selective targeting of AML cells.
Several targeting strategies were investigated, including antibody-based delivery using CD33-directed constructs, cell-penetrating peptide and sialic acid analogue. These studies enabled a systematic evaluation of intracellular delivery, target engagement and release of the active payload in cellular systems.
Additional medicinal chemistry efforts expanded the original scope of the project to include covalent DPP9 inhibitors. This allowed direct comparison between covalent and non-covalent inhibition strategies and provided new insights into the role of target residence time in determining biological activity.
The project also investigated cleavable linker technologies and intracellular drug release mechanisms, identifying several key parameters that influence the effectiveness of targeted delivery systems. Furthermore, comparative studies between inhibition and degradation strategies improved our understanding of how different modes of DPP9 modulation affect pyroptosis induction and therapeutic response.
Although additional optimization of delivery efficiency and payload release is still required, the project generated important knowledge for the future development of selective DPP9-targeting therapeutics and pyroptosis-based treatment strategies.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

The project advances the state of the art in several areas of medicinal chemistry and targeted drug delivery.
First, it represents one of the first systematic investigations of selective DPP9-targeting delivery strategies for the induction of pyroptosis in AML cells.
Second, the project generated new chemical tools for the investigation of target residence time by directly comparing covalent and non-covalent DPP9 inhibitors and evaluating how different target engagement mechanisms influence biological responses.
Third, the work highlighted the critical role of linker stability, intracellular drug release and delivery efficiency in determining the performance of targeted therapeutic systems.
Finally, by comparing conventional inhibition with targeted degradation approaches, the project provided new knowledge on how different modes of DPP9 modulation influence pyroptosis induction and therapeutic outcome.
These findings provide a valuable framework for the future development of DPP9-targeting therapeutics, targeted delivery technologies and next-generation precision medicines.