The CIpP activator, TR-57, is highly effective as a single agent and in combination with venetoclax against CLL cells in vitro.
Leuk Lymphoma
; 65(5): 585-597, 2024 May.
Article
en En
| MEDLINE
| ID: mdl-38227293
ABSTRACT
Despite advances in treatment, a significant proportion of patients with chronic lymphocytic leukemia (CLL) will relapse with drug-resistant disease. The imipridones, ONC-201 and ONC-212, are effective against a range of different cancers, including acute myeloid leukemia (AML) and tumors of the brain, breast, and prostate. These drugs induce cell death through activation of the mitochondrial protease, caseinolytic protease (CIpP), and the unfolded protein response (UPR). Here we demonstrate that the novel imipridone analog, TR-57, has efficacy as a single agent and synergises with venetoclax against CLL cells under in vitro conditions that mimic the tumor microenvironment. Changes in protein expression suggest TR-57 activates the UPR, inhibits the AKT and ERK1/2 pathways and induces pro-apoptotic changes in the expression of proteins of the BCL-2 family. The study suggests that TR-57, as a single agent and in combination with venetoclax, may represent an effective treatment option for CLL.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Sulfonamidas
/
Leucemia Linfocítica Crónica de Células B
/
Apoptosis
/
Compuestos Bicíclicos Heterocíclicos con Puentes
/
Sinergismo Farmacológico
Límite:
Humans
Idioma:
En
Revista:
Leuk Lymphoma
/
Leuk. lymphoma
/
Leukemia and lymphoma
Asunto de la revista:
HEMATOLOGIA
/
NEOPLASIAS
Año:
2024
Tipo del documento:
Article
País de afiliación:
Australia