Multi-Kinase Inhibitor with Anti-p38? Activity in Cutaneous T-Cell Lymphoma.

ABSTRACT: Current cutaneous T-cell lymphoma (CTCL) therapies are marked by an abbreviated response, subsequent drug resistance, and poor prognosis for patients with advanced disease. An understanding of molecular regulators involved in CTCL is needed to develop effective targeted therapies. One candidate regulator is p38?, a mitogen-activated protein kinase crucial for malignant T-cell activity and growth. p38? gene expression is selectively increased in CTCL patient samples and cell lines but not in healthy T cells. In addition, gene silencing of p38? reduced CTCL cell viability, showing a key role in CTCL pathogenesis. Screening p38? inhibitors is critical for understanding the mechanism of CTCL tumorigenesis and developing therapeutic applications. We prioritized a potent p38? inhibitor (F7, also known as PIK75) through a high-throughput kinase inhibitor screen. At nanomolar concentrations, PIK75, a multiple kinase inhibitor, selectively killed CD4+ malignant CTCL cells but spared healthy CD4+ cells; induced significant reduction of tumor size in mouse xenografts; and effectively inhibited p38? enzymatic activity and phosphorylation of its substrate, DLGH1, in CTCL cells and mouse xenografts. Here, we report that PIK75 has a potential clinical application to serve as a scaffold molecule for the development of a more selective p38? inhibitor.

SUBMITTER: Zhang XH 

PROVIDER: S-EPMC7269016 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature