Research team

Expertise

Medicinal chemistry focused on targeted protein degradation. Design and synthesis of compounds that destine a protein of interest to degradation via the ubiquitin-proteasome system or the autophagy machinery. Characterization of the degradation mechanism in representative cellular lines.

AUTAC- and PROTAC-mediated degradation of DPP9 to induce pyroptosis: a novel treatment strategy in acute myeloid leukemia. 01/10/2023 - 30/09/2026

Abstract

Dipeptidyl-peptidase 9 (DPP9) is a proline-selective serine protease. Recently, DPP9 inhibition has shown to cause pyroptosis selectively in acute myeloid leukemia cells. Pyroptosis is a lytic form of programmed cell death. The process typically recruits immune cells and inflammatory mediators, causing a localized activation of the innate immune system. This is appealing for leukemia treatment, because the immune-response to leukemic cells is typically subdued. Recent mechanistic insight shows that DPP9 suppresses pyroptosis through a stabilizing protein-protein interaction (PPI) with the NLRP1 and CARD8 inflammasome sensors. DPP9 inhibition mildly impairs the interaction, causing some NLRP1 and CARD8 release and induction of pyroptosis. We hypothesize that clearance of DPP9 from the cytoplasm could be a more effective way of causing pyroptosis than inhibition. To this end, PROTAC and AUTAC approaches will be pursued in this project. PROTACs and AUTACs are heterobifunctional molecules that mediate the degradation of a protein of interest (POI) by hijacking the cell's own proteasome and autophagic system, respectively. The project covers preparation and in depth biological investigation of the novel molecules. It can be expected to significantly advance the state-of-the art in the field of DPP9 research, targeted protein degradation and leukemia therapy.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project