Descrizione del progetto
Indurre la morte cellulare nelle cellule leucemiche
La leucemia mieloide acuta (LMA) è un tipo di cancro del sangue che colpisce il midollo osseo e le cellule del sangue ma, come per molti tumori, il sistema immunitario non è efficace nel riconoscere ed eliminare le cellule leucemiche. La piroptosi, una forma litica di morte cellulare programmata, innesca il rilascio di segnali infiammatori che attirano le cellule immunitarie innate verso il sito di morte cellulare e possono contribuire a uccidere le cellule tumorali. Finanziato dal programma di azioni Marie Skłodowska-Curie, il progetto DPP9-TACDrug si concentrerà sulla dipeptidil peptidasi 9 (DPP9), un enzima responsabile della soppressione della piroptosi. Il progetto si propone di sviluppare una strategia per degradare la DPP9 e indurre la piroptosi come percorso preferenziale per trattare la LMA e altri tipi di cancro.
Obiettivo
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.
Campo scientifico
Parole chiave
Programma(i)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Meccanismo di finanziamento
MSCA-PF - MSCA-PFCoordinatore
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