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Targeting the Non-ATP-binding Pocket of the MAP Kinase P38γ Mediates a Novel Mechanism of Cytotoxicity in Cutaneous T-cell Lymphoma (CTCL)

Overview
Journal FEBS Lett
Specialty Biochemistry
Date 2021 Aug 29
PMID 34455585
Citations 4
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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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