A thiazole-derived oridonin analogue exhibits antitumor activity by directly and allosterically inhibiting STAT3

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	A thiazole-derived oridonin analogue exhibits antitumor activity by directly and allosterically inhibiting STAT3
	Shen, XF; Zhao, L; Chen, PH; Gong, YQ; Liu, DD; Zhang, X; Dai, LZ; Sun, QX; Lou, JZ; Jin, Z; Zhang, BH; Niu, DW; Chen, CS; Qi, XB; Jia, D
	2019
发表期刊	JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN	0021-9258
卷号	294 期号:46 页码:17471-17486
摘要	Constitutive activation of signal transducer and activator of transcription 3 (STAT3) occurs in similar to 70% of human cancers, and STAT3 is regarded as one of the most promising targets for cancer therapy. However, specific direct STAT3 inhibitors remain to be developed. Oridonin is an ent-kaurane plant-derived diterpenoid with anti-cancer and anti-inflammatory activities. Here, using an array of cell-based and biochemical approaches, including cell proliferation and apoptosis assays, pulldown and reporter gene assays, site-directed mutagenesis, and molecular dynamics analyses, we report that a thiazole-derived oridonin analogue, CYD0618, potently and directly inhibits STAT3. We found that CYD0618 covalently binds to Cys-542 in STAT3 and suppresses its activity through an allosteric effect, effectively reducing STAT3 dimerization and nuclear translocation, as well as decreasing expression of STAT3-targeted oncogenes. Remarkably, CYD0618 not only strongly inhibited growth of multiple cancer cell lines that harbor constitutive STAT3 activation, but it also suppressed in vivo tumor growth via STAT3 inhibition. Taken together, our findings suggest Cys-542 as a druggable site for selectively inhibiting STAT3 and indicate that CYD0618 represents a promising lead compound for developing therapeutic agents against STAT3-driven diseases.
收录类别	SCI
语种	英语
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/12979
专题	科研部门_肿瘤生物学（陈策实）
推荐引用方式 GB/T 7714	Shen, XF,Zhao, L,Chen, PH,et al. A thiazole-derived oridonin analogue exhibits antitumor activity by directly and allosterically inhibiting STAT3[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2019,294(46):17471-17486.
APA	Shen, XF.,Zhao, L.,Chen, PH.,Gong, YQ.,Liu, DD.,...&Jia, D.(2019).A thiazole-derived oridonin analogue exhibits antitumor activity by directly and allosterically inhibiting STAT3.JOURNAL OF BIOLOGICAL CHEMISTRY,294(46),17471-17486.
MLA	Shen, XF,et al."A thiazole-derived oridonin analogue exhibits antitumor activity by directly and allosterically inhibiting STAT3".JOURNAL OF BIOLOGICAL CHEMISTRY 294.46(2019):17471-17486.

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