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

DPP9 (dipeptidyl peptidase 9) is a cytosolic serine protease. It recognizes and cleaves N-terminal dipeptides containing proline at the penultimate position.

The enzyme is currently receiving strong international attention after it was reported that DPP9 inhibition induces inflammatory cell death (pyroptosis) in Acute Myeloid Leukemia (AML) cells. Pyroptosis is a lytic form of cell death that also causes a pronounced, local upregulation of the innate immune system.

This is of particular interest to leukemia treatment because the immune response to leukemic cells is strongly suppressed.

Very recently, however, reports have been published that identify other, non-cancerous cell types that also undergo pyroptosis upon DPP9 inhibition. This raises questions on how selective and safe DPP9 inhibition can be as a therapeutic strategy in AML.

The host reported the first selective, nanomolar DPP9 inhibitors in 2023 and also discovered the first DPP9-degrading PROTACs (unpublished data).

PyroVectors mission is to selectively unleash these molecules pyroptosis induction potential against AML cells, by delivering them towards these cells with vector approaches.

Given the general lack of knowledge on how to optimally target small molecules to AML cells, three molecules that recognize AML cells will be compared as vectors for DPP9 inhibitors: a monoclonal antibody, an AML cell-penetrating peptide, and a sialic acid analog.

DPP9 inhibitors that are covalently linked to these 3 ligands, will be investigated in terms of internalization and pyroptosis induction in cells.

Furthermore, AML selectivity and therapeutic potential in vivo will be characterized with the ultimate aim of validating the approach as a safe and effective therapeutic strategy for AML.

Overall we are strongly convinced that this project can be an essential step toward a patient-friendly application of DPP9 inhibition or degradation in AML.