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

Project Information

PyroVector

Grant agreement ID: 101155555

DOI

10.3030/101155555

Project closed

EC signature date 8 March 2024

Start date 1 May 2024

End date 30 April 2026

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 191 760,00

Coordinated by

UNIVERSITEIT ANTWERPEN
Belgium

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

Reporting period: 2024-05-01 to 2026-04-30

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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.