A natural compound derivative P-13 inhibits STAT3 signaling by covalently inhibiting Janus kinase 2

doi:10.1007/s10637-018-0637-2

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	A natural compound derivative P-13 inhibits STAT3 signaling by covalently inhibiting Janus kinase 2
	Huang, Hui 2; Niu, Junxing 2; Wang, Fei 2; Hu, Lihong 1; Yu, Qiang2
刊名	Investigational new drugs
	2018-08-03
ISSN号	1573-0646
DOI	10.1007/s10637-018-0637-2
文献子类	Article
英文摘要	We investigated the function and molecular mechanisms of 2-desoxy-4β-propylcarbamate-pulchellin (P-13), a sesquiterpene lactone derivative of 2-desoxy-4-epi-pulchellin from the traditional Chinese medicinal herb Carpesium abrotanoides L, in regulating STAT3 signaling and cancer cell growth. We found that P-13 inhibited the IL-6-induced, as well as the constitutive, STAT3 activation in a dose and time-dependent manner. In vitro kinase activity analyses demonstrated that P-13 directly inhibited JAK2 kinase activity. The inhibitory effects of P-13 on JAK2/STAT3 signaling could be blocked by reducing agents dithiothreitol (DTT) or glutathione (GSH), indicating an involvement of the thiol-reactive α-β unsaturated carbonyl group in P-13. Further analyses with mass spectrograph, as well as molecular docking, revealed that P-13 covalently bound with the C452 in the SH2 domain of JAK2. Furthermore, P-13 inhibited growth and induced death of many cancer cell lines, particularly those expressing constitutively activated STAT3. It also inhibited in vivo growth of human cancer cell xenografts. Taken together, these findings revealed P-13 as a novel covalent inhibitor of JAK2, uncovered a new mechanism to inhibit JAK2, and provided a promising anti-cancer drug candidate.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/266251]
专题	药理学第一研究室
通讯作者	Hu, Lihong; Yu, Qiang
作者单位	1.Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, 210046, Jiangsu Province, China 2.Division of Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China;
推荐引用方式 GB/T 7714	Huang, Hui,Niu, Junxing,Wang, Fei,et al. A natural compound derivative P-13 inhibits STAT3 signaling by covalently inhibiting Janus kinase 2[J]. Investigational new drugs,2018.
APA	Huang, Hui,Niu, Junxing,Wang, Fei,Hu, Lihong,&Yu, Qiang.(2018).A natural compound derivative P-13 inhibits STAT3 signaling by covalently inhibiting Janus kinase 2.Investigational new drugs.
MLA	Huang, Hui,et al."A natural compound derivative P-13 inhibits STAT3 signaling by covalently inhibiting Janus kinase 2".Investigational new drugs (2018).