Targeting the non-ATP-binding pocket of the MAP kinase p38γ mediates a novel mechanism of cytotoxicity in cutaneous T-cell lymphoma (CTCL).
FEBS Lett
; 595(20): 2570-2592, 2021 10.
Article
em En
| MEDLINE
| ID: mdl-34455585
ABSTRACT
We describe here for the first time a lipid-binding-domain (LBD) in p38γ mitogen-activated protein kinase (MAPK) involved in the response of T cells to a newly identified inhibitor, CSH71. We describe how CSH71, which binds to both the LBD and the ATP-binding pocket of p38γ, is selectively cytotoxic to CTCL Hut78 cells but spares normal healthy peripheral blood mononuclear (PBMC) cells, and propose possible molecular mechanisms for its action. p38γ is a key player in CTCL development, and we expect that the ability to regulate its expression by specifically targeting the lipid-binding domain will have important clinical relevance. Our findings characterize novel mechanisms of gene regulation in T lymphoma cells and validate the use of computational screening techniques to identify inhibitors for therapeutic development.
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MEDLINE
Assunto principal:
Neoplasias Cutâneas
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Trifosfato de Adenosina
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Linfoma Cutâneo de Células T
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Proteína Quinase 12 Ativada por Mitógeno
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article