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DPP9 degradation-induced pyroptosis for treatment of acute myeloid leukemia

Project description

Inducing cell death in leukaemia cells

Acute myeloid leukaemia (AML) is a type of blood cancer that affects the bone marrow and blood cells, and, as with many cancers, the immune system is not effective in recognising and eliminating leukaemia cells. Pyroptosis, a lytic form of programmed cell death, triggers the release of inflammatory signals that attract innate immune cells to the site of cell death and can help kill cancer cells. Funded by the Marie Skłodowska-Curie Actions programme, the DPP9-TACDrug project will focus on dipeptidyl peptidase 9 (DPP9), an enzyme responsible for suppressing pyroptosis. The project proposes to develop a strategy to degrade DPP9 and induce pyroptosis as a better way to treat AML and other types of cancer.

Objective

Dipeptidyl-peptidase 9 (DPP9) is a proline-selective serine protease that belongs to the peptidase S9 family. During recent years, DPP9 inhibition has shown to cause pyroptosis, selectively in acute myeloid leukemia cells. Pyroptosis is a lytic form of programmed cell death, that has mainly been observed in immune cells. The process typically recruits and activates other immune cells and inflammatory mediators, causing a localized activation of the innate immune system. This is particularly appealing for leukemia treatment, because the immune-response to leukemic cells is typically severely subdued. Recent mechanistic insight suggests that native DPP9 suppresses pyroptosis through a stabilizing protein-protein interaction (PPI) with the NLRP1 inflammasome sensor. Furthermore, DPP9 inhibition with small molecules only has a mildly destabilizing effect on the [DPP9-NLRP1] PPI.
This proposal suggests the targeted clearance of DPP9 from the cytoplasm in acute myeloid leukemia cells to cause pyroptosis through enhanced NLRP1 activation. PROTACs and AUTACs are heterobifunctional molecules that mediate the degradation of a protein of interest (POI) by hijacking cell’s own proteasome and autophagic system, respectively. The implementation of PROTAC and AUTAC technologies for targeted clearance of DPP9 and consequent pyroptosis induction in acute myeloid leukemia cell lines is proposed in this project. PROTAC and AUTAC molecules will be designed and synthesized, followed by in vitro evaluation of their cell permeability, DPP9-engagement, DPP9 clearance potency and selectivity, and dose/time dependence of DPP9 clearance. Furthermore, a comparison of the pyroptosis signatures of PROTACs, AUTACs and DPP9 inhibitors will be performed. Overall, this proposal can provide a superior therapeutic strategy to AML and other cancer types.

Funding Scheme

MSCA-PF - MSCA-PF

Coordinator

UNIVERSITEIT ANTWERPEN
Net EU contribution
€ 191 760,00
Address
Prinsstraat 13
2000 Antwerpen
Belgium

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Region
Vlaams Gewest Prov. Antwerpen Arr. Antwerpen
Activity type
Higher or Secondary Education Establishments
Links
Other funding
€ 0,00