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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.
Sci Rep. 2016 Dec 05; 6(1):3.SR

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.

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Authors+Show Affiliations

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. Northwestern University, Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, Illinois, 60611, USA.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. zhanglanx_9@126.com.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. ouyangliang@scu.edu.cn.

MeSH

AnimalsApoptosisCell Line, TumorCell MovementCell ProliferationDibenzoxepinsDrug DesignHumansHydrazinesMice, Inbred BALB CMice, NudeMolecular Docking SimulationMolecular Dynamics SimulationNeoplasm TransplantationPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsStructure-Activity RelationshipTriple Negative Breast Neoplasms

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28442756

Citation

Fu, Leilei, et al. "Crystal Structure-based Discovery of a Novel Synthesized PARP1 Inhibitor (OL-1) With Apoptosis-inducing Mechanisms in Triple-negative Breast Cancer." Scientific Reports, vol. 6, no. 1, 2016, p. 3.

Fu L, Wang S, Wang X, et al. Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer. Sci Rep. 2016;6(1):3.

Fu, L., Wang, S., Wang, X., Wang, P., Zheng, Y., Yao, D., Guo, M., Zhang, L., & Ouyang, L. (2016). Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer. Scientific Reports, 6(1), 3. https://doi.org/10.1038/s41598-016-0007-2

Fu L, et al. Crystal Structure-based Discovery of a Novel Synthesized PARP1 Inhibitor (OL-1) With Apoptosis-inducing Mechanisms in Triple-negative Breast Cancer. Sci Rep. 2016 Dec 5;6(1):3. PubMed PMID: 28442756.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer. AU - Fu,Leilei, AU - Wang,Shuya, AU - Wang,Xuan, AU - Wang,Peiqi, AU - Zheng,Yaxin, AU - Yao,Dahong, AU - Guo,Mingrui, AU - Zhang,Lan, AU - Ouyang,Liang, Y1 - 2016/12/05/ PY - 2016/04/20/received PY - 2016/08/24/accepted PY - 2017/4/27/entrez PY - 2017/4/27/pubmed PY - 2018/1/30/medline SP - 3 EP - 3 JF - Scientific reports JO - Sci Rep VL - 6 IS - 1 N2 - 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. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/28442756/Crystal_structure_based_discovery_of_a_novel_synthesized_PARP1_inhibitor__OL_1__with_apoptosis_inducing_mechanisms_in_triple_negative_breast_cancer_ L2 - https://doi.org/10.1038/s41598-016-0007-2 DB - PRIME DP - Unbound Medicine ER -