Description du projet
Induire la mort cellulaire dans les cellules leucémiques
La leucémie aiguë myéloblastique (LAM) est un type de cancer du sang qui touche la moelle osseuse et les cellules sanguines et, à l’instar de nombreux cancers, le système immunitaire ne parvient pas à reconnaître et à éliminer efficacement les cellules leucémiques. La pyroptose, une forme lytique de mort cellulaire programmée, déclenche la libération de signaux inflammatoires qui attirent les cellules immunitaires innées vers le site de la mort cellulaire et peuvent contribuer à éliminer les cellules cancéreuses. Financé par le programme Actions Marie Skłodowska-Curie, le projet DPP9-TACDrug s’intéressera tout particulièrement à la dipeptidyl peptidase-9 (DPP9), une enzyme responsable de la suppression de la pyroptose. Le projet propose d’élaborer une stratégie permettant de dégrader la DPP9 et d’induire la pyroptose en tant que moyen plus efficace de traiter la LAM et d’autres types de cancer.
Objectif
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.
Champ scientifique
Mots‑clés
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régime de financement
MSCA-PF - MSCA-PFCoordinateur
2000 Antwerpen
Belgique