DPP9-TACDrug
Financiado
DPP9 degradation-induced pyroptosis for treatment of acute myeloid leukemia
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. Pyropto...
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.
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Duración del proyecto: 24 meses
Fecha Inicio: 2023-03-05
Fecha Fin: 2025-03-31
Fecha Fin: 2025-03-31
Línea de financiación: concedida
El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2023-03-05
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
HORIZON-MSCA-2022-PF-01-01:
MSCA Postdoctoral Fellowships 2022
Cerrada
hace 2 años
Presupuesto
El presupuesto total del proyecto asciende a
192K€
Líder del proyecto
UNIVERSITEIT ANTWERPEN
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5