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Title 

Inhibition of STAT3 activation by KT-18618 via the disruption of the interaction between JAK3 and STAT3

 

STAT3 저해 물질 KT-18618의 활성 기전 규명

Authors 

Dae Seop ShinSeung Nam JungJi Eun YunChang Woo LeeDong Cho HanB KimY K MinN S KangByoung-Mog Kwon

Publisher 

Elsevier

Issue Date 

2014

Citation 

Biochemical Pharmacology, vol. 89, no. 1, pp. 62-73

Keywords 

ApoptosisBreast cancerJAK3STAT3

Abstract 

The constitutive activation of STAT3 in human cancers causes the abnormal proliferation and survival of cancer cells, and thus, STAT3 is a therapeutic target of antitumor drugs. We screened a small-molecule library of 8600 synthetic compounds from the "Korea Chemical Bank" to identify inhibit STAT3 activity using a cell-based luciferase assay system. KT-18618 ((Z)-N-(4-chlorophenyl)-N-methyl-2-[1,3,3,3,-tetrafluoro-2-(thiophen-2-yl) prop-1-enyloxy]-acetamide) was selected as a novel inhibitor of the JAK/STAT3 pathway. KT-18618 inhibited STAT3 phosphorylation and the expression of STAT3-regulated genes. The inhibition of STAT3 phosphorylation led to the apoptosis of MDA-MB-468 cells. We postulated that the inhibition of the JAK family of proteins or c-Src inhibited STAT3 phosphorylation. Interestingly, the phosphorylation of these kinases was only mildly inhibited, but the phosphorylation of STAT3 was completely inhibited. This result implies that the inhibition of STAT3 phosphorylation by KT-18618 is an independent event that occurs through the phosphorylation of upstream kinases. Co-immunoprecipitation experiments revealed that KT-18618 inhibited the JAK3-STAT3 interaction. Moreover, JAK3 molecules were captured by biotinylated KT-18618, implying that KT-18618 bound to JAK3 molecules. Additionally, 1 μM KT-18618 inhibited JAK3 kinase activity by approximately 28% in an in vitro kinase assay. From these results, we suggest that KT-18618 binds to JAK3 molecules and disrupts the JAK3-STAT3 interaction, which leads to the inhibition of STAT3 phosphorylation. KT-18618 is the first inhibitor of the JAK3-STAT3 interaction.

ISSN 

0006-2952

Link 

http://dx.doi.org/10.1016/j.bcp.2014.02.017

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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