Identification of New Shikonin Derivatives as Antitumor Agents Targeting STAT3 SH2 Domain

Abstract Signal transducer and activator of transcription 3 (STAT3) is hyper-activated in diversiform human tumors and has been validated as an attractive therapeutic target. Current research showed that a natural product, shikonin, along with its synthetic analogues, is able to inhibit the activity...

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Autores principales:	Han-Yue Qiu, Xiang Zhu, Yue-Lin Luo, Hong-Yan Lin, Cheng-Yi Tang, Jin-Liang Qi, Yan-Jun Pang, Rong-Wu Yang, Gui-Hua Lu, Xiao-Ming Wang, Yong-Hua Yang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/aff6189e0a284adcb62ed7e81cccab4e
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spelling	oai:doaj.org-article:aff6189e0a284adcb62ed7e81cccab4e2021-12-02T12:32:41ZIdentification of New Shikonin Derivatives as Antitumor Agents Targeting STAT3 SH2 Domain10.1038/s41598-017-02671-72045-2322https://doaj.org/article/aff6189e0a284adcb62ed7e81cccab4e2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02671-7https://doaj.org/toc/2045-2322Abstract Signal transducer and activator of transcription 3 (STAT3) is hyper-activated in diversiform human tumors and has been validated as an attractive therapeutic target. Current research showed that a natural product, shikonin, along with its synthetic analogues, is able to inhibit the activity of STAT3 potently. The potential space of shikonin in developing novel anti-cancer agents encouraged us to carry out the investigation of the probable binding mode with STAT3. From this foundation, we have designed new types of STAT3 SH2 inhibitors. Combined simulations were performed to filter for the lead compound, which was then substituted, synthesized and evaluated by a variety of bioassays. Among the entities, PMM-172 exhibited the best anti-proliferative activity against MDA-MB-231 cells with IC50 value 1.98 ± 0.49 μM. Besides, it was identified to decrease luciferase activity, induce cell apoptosis and reduce mitochondrial transmembrane potential in MDA-MB-231 cells. Also, PMM-172 inhibited constitutive/inducible STAT3 activation without affecting STAT1 and STAT5 in MDA-MB-231 cells, and had no effect in non-tumorigenic MCF-10A cells. Moreover, PMM-172 suppressed STAT3 nuclear localization and STAT3 downstream target genes expression. Overall, these results indicate that the antitumor activity of PMM-172 is at least partially due to inhibition of STAT3 in breast cancer cells.Han-Yue QiuXiang ZhuYue-Lin LuoHong-Yan LinCheng-Yi TangJin-Liang QiYan-Jun PangRong-Wu YangGui-Hua LuXiao-Ming WangYong-Hua YangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Han-Yue Qiu Xiang Zhu Yue-Lin Luo Hong-Yan Lin Cheng-Yi Tang Jin-Liang Qi Yan-Jun Pang Rong-Wu Yang Gui-Hua Lu Xiao-Ming Wang Yong-Hua Yang Identification of New Shikonin Derivatives as Antitumor Agents Targeting STAT3 SH2 Domain
description	Abstract Signal transducer and activator of transcription 3 (STAT3) is hyper-activated in diversiform human tumors and has been validated as an attractive therapeutic target. Current research showed that a natural product, shikonin, along with its synthetic analogues, is able to inhibit the activity of STAT3 potently. The potential space of shikonin in developing novel anti-cancer agents encouraged us to carry out the investigation of the probable binding mode with STAT3. From this foundation, we have designed new types of STAT3 SH2 inhibitors. Combined simulations were performed to filter for the lead compound, which was then substituted, synthesized and evaluated by a variety of bioassays. Among the entities, PMM-172 exhibited the best anti-proliferative activity against MDA-MB-231 cells with IC50 value 1.98 ± 0.49 μM. Besides, it was identified to decrease luciferase activity, induce cell apoptosis and reduce mitochondrial transmembrane potential in MDA-MB-231 cells. Also, PMM-172 inhibited constitutive/inducible STAT3 activation without affecting STAT1 and STAT5 in MDA-MB-231 cells, and had no effect in non-tumorigenic MCF-10A cells. Moreover, PMM-172 suppressed STAT3 nuclear localization and STAT3 downstream target genes expression. Overall, these results indicate that the antitumor activity of PMM-172 is at least partially due to inhibition of STAT3 in breast cancer cells.
format	article
author	Han-Yue Qiu Xiang Zhu Yue-Lin Luo Hong-Yan Lin Cheng-Yi Tang Jin-Liang Qi Yan-Jun Pang Rong-Wu Yang Gui-Hua Lu Xiao-Ming Wang Yong-Hua Yang
author_facet	Han-Yue Qiu Xiang Zhu Yue-Lin Luo Hong-Yan Lin Cheng-Yi Tang Jin-Liang Qi Yan-Jun Pang Rong-Wu Yang Gui-Hua Lu Xiao-Ming Wang Yong-Hua Yang
author_sort	Han-Yue Qiu
title	Identification of New Shikonin Derivatives as Antitumor Agents Targeting STAT3 SH2 Domain
title_short	Identification of New Shikonin Derivatives as Antitumor Agents Targeting STAT3 SH2 Domain
title_full	Identification of New Shikonin Derivatives as Antitumor Agents Targeting STAT3 SH2 Domain
title_fullStr	Identification of New Shikonin Derivatives as Antitumor Agents Targeting STAT3 SH2 Domain
title_full_unstemmed	Identification of New Shikonin Derivatives as Antitumor Agents Targeting STAT3 SH2 Domain
title_sort	identification of new shikonin derivatives as antitumor agents targeting stat3 sh2 domain
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/aff6189e0a284adcb62ed7e81cccab4e
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Identification of New Shikonin Derivatives as Antitumor Agents Targeting STAT3 SH2 Domain

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