Descripción del proyecto
Inducción de la muerte celular en las células leucémicas
La leucemia mieloide aguda (LMA) es un tipo de neoplasia hemática que afecta a la médula ósea y a los glóbulos sanguíneos y, como ocurre con muchos tipos de cáncer, el sistema inmunitario no es eficaz para reconocer y eliminar las células leucémicas. La piroptosis, una forma lítica de muerte celular programada, desencadena la liberación de señales inflamatorias que atraen a las células inmunitarias innatas al lugar de la muerte celular y pueden ayudar a destruir las células cancerosas. El equipo del proyecto RECoil3D, financiado por las acciones Marie Skłodowska-Curie, se centrará en la dipeptidil peptidasa 9 (DPP9), una enzima responsable de la supresión de la piroptosis. En el proyecto se propone desarrollar una estrategia para degradar la DPP9 e inducir la piroptosis como una forma más eficiente de tratar la LMA y otros tipos de cáncer.
Objetivo
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.
Ámbito científico
Palabras clave
Programa(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régimen de financiación
MSCA-PF - MSCA-PFCoordinador
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