Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer

Abstract Poly (ADP-ribose) polymerase-1 (PARP1) is a highly conserved enzyme focused on the self-repair of cellular DNA damage. Until now, numbers of PARP inhibitors have been reported and used for breast cancer therapy in recent years, especially in TNBC. However, developing a new type PARP inhibit...

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Autores principales:	Leilei Fu, Shuya Wang, Xuan Wang, Peiqi Wang, Yaxin Zheng, Dahong Yao, Mingrui Guo, Lan Zhang, Liang Ouyang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2016
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/37c5cbb7ec024a42a59c6428798e545c
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spelling	oai:doaj.org-article:37c5cbb7ec024a42a59c6428798e545c2021-12-02T11:40:15ZCrystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer10.1038/s41598-016-0007-22045-2322https://doaj.org/article/37c5cbb7ec024a42a59c6428798e545c2016-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-016-0007-2https://doaj.org/toc/2045-2322Abstract Poly (ADP-ribose) polymerase-1 (PARP1) is a highly conserved enzyme focused on the self-repair of cellular DNA damage. Until now, numbers of PARP inhibitors have been reported and used for breast cancer therapy in recent years, especially in TNBC. However, developing a new type PARP inhibitor with distinctive skeleton is alternatively promising strategy for TNBC therapy. In this study, based on co-crystallization studies and pharmacophore-docking-based virtual screening, we discovered a series of dihydrodibenzo[b,e]-oxepin compounds as PARP1 inhibitors. Lead optimization result in the identification of compound OL-1 (2-(11-(3-(dimethylamino)propylidene)-6,11- dihydrodibenzo[b,e]oxepin )-2-yl)acetohydrazide), which has a novel chemical scaffold and unique binding interaction with PARP1 protein. OL-1 demonstrated excellent potency (inhibiting PARP1 enzyme activity with IC50 = 0.079 μM), as well as inhibiting PARP-modulated PARylation and cell proliferation in MDA-MB-436 cells (BRAC1 mutation). In addition, OL-1 also inhibited cell migration that closely related to cancer metastasis and displayed remarkable anti-tumor efficacy in MDA-MB-436 xenograft model without apparent toxicities. These findings highlight a new small-molecule PAPR1 inhibitor (OL-1) that has the potential to impact future TNBC therapy.Leilei FuShuya WangXuan WangPeiqi WangYaxin ZhengDahong YaoMingrui GuoLan ZhangLiang OuyangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 6, Iss 1, Pp 1-15 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Leilei Fu Shuya Wang Xuan Wang Peiqi Wang Yaxin Zheng Dahong Yao Mingrui Guo Lan Zhang Liang Ouyang Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer
description	Abstract Poly (ADP-ribose) polymerase-1 (PARP1) is a highly conserved enzyme focused on the self-repair of cellular DNA damage. Until now, numbers of PARP inhibitors have been reported and used for breast cancer therapy in recent years, especially in TNBC. However, developing a new type PARP inhibitor with distinctive skeleton is alternatively promising strategy for TNBC therapy. In this study, based on co-crystallization studies and pharmacophore-docking-based virtual screening, we discovered a series of dihydrodibenzo[b,e]-oxepin compounds as PARP1 inhibitors. Lead optimization result in the identification of compound OL-1 (2-(11-(3-(dimethylamino)propylidene)-6,11- dihydrodibenzo[b,e]oxepin )-2-yl)acetohydrazide), which has a novel chemical scaffold and unique binding interaction with PARP1 protein. OL-1 demonstrated excellent potency (inhibiting PARP1 enzyme activity with IC50 = 0.079 μM), as well as inhibiting PARP-modulated PARylation and cell proliferation in MDA-MB-436 cells (BRAC1 mutation). In addition, OL-1 also inhibited cell migration that closely related to cancer metastasis and displayed remarkable anti-tumor efficacy in MDA-MB-436 xenograft model without apparent toxicities. These findings highlight a new small-molecule PAPR1 inhibitor (OL-1) that has the potential to impact future TNBC therapy.
format	article
author	Leilei Fu Shuya Wang Xuan Wang Peiqi Wang Yaxin Zheng Dahong Yao Mingrui Guo Lan Zhang Liang Ouyang
author_facet	Leilei Fu Shuya Wang Xuan Wang Peiqi Wang Yaxin Zheng Dahong Yao Mingrui Guo Lan Zhang Liang Ouyang
author_sort	Leilei Fu
title	Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer
title_short	Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer
title_full	Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer
title_fullStr	Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer
title_full_unstemmed	Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer
title_sort	crystal structure-based discovery of a novel synthesized parp1 inhibitor (ol-1) with apoptosis-inducing mechanisms in triple-negative breast cancer
publisher	Nature Portfolio
publishDate	2016
url	https://doaj.org/article/37c5cbb7ec024a42a59c6428798e545c
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Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer

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