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Discovery, mechanism and metabolism studies of 2,3-difluorophenyl-linker-containing PARP1 inhibitors with enhanced in vivo efficacy for cancer therapy.
Eur J Med Chem. 2017 Sep 29; 138:514-531.EJ

Abstract

Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially breast and ovarian cancers, and tumor cell lines deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, with the help of molecular docking, we identified a novel series of 2,3-difluorophenyl-linker analogues (15-54) derived from olaparib (1) as PARP1 inhibitors. Lead optimization led to the identification of 47, which showed high selectivity and high potency against PARP1 enzyme (IC50 = 1.3 nM), V-C8 cells (IC50 = 0.003 nM), Capan-1 cells (IC50 = 7.1 nM) and MDA-MB-436 cells (IC50 = 0.2 nM). Compound 47 had more potent PARP1-DNA trapping and double-strand breaks (DSBs)-induction activities than 1 and induced G2/M arrest and caspase-dependent apoptosis. Compound 47 (50 mg/kg, 94.2%) had a more beneficial effect on tumor growth inhibition than 1 (100 mg/kg, 65.0%) in a BRCA1-mutated xenograft model and significantly inhibited tumor growth (40 mg/kg, 48.1%) in a BRCA2-mutated xenograft model, with no negative influence on the body weight of the mice. Collectively, these data demonstrated that 47 might be an excellent drug candidate for the treatment of cancer, especially for BRCA-deficient tumors.

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Chen W
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
Guo N
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Qi M
Laboratory of Pharmaceutical Crystal Engineering & Technology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
Dai H
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
Hong M
Laboratory of Pharmaceutical Crystal Engineering & Technology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
Guan L
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
Huan X
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Song S
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
He J
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Wang Y
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Xi Y
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Yang X
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Shen Y
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Su Y
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Sun Y
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Gao Y
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Chen Y
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Ding J
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Tang Y
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
Ren G
Laboratory of Pharmaceutical Crystal Engineering & Technology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: rgb@ecust.edu.cn.
Miao Z
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: zhmiao@simm.ac.cn.
Li J
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: jianli@ecust.edu.cn.

MeSH

AnimalsAntineoplastic AgentsCell Line, TumorCell ProliferationDose-Response Relationship, DrugDrug DiscoveryDrug Screening Assays, AntitumorHumansMaleMiceMice, NudeMolecular StructureNeoplasms, ExperimentalPhthalazinesPiperazinesPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsRatsRats, Sprague-DawleyStructure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28692916

Citation

Chen, Wenhua, et al. "Discovery, Mechanism and Metabolism Studies of 2,3-difluorophenyl-linker-containing PARP1 Inhibitors With Enhanced in Vivo Efficacy for Cancer Therapy." European Journal of Medicinal Chemistry, vol. 138, 2017, pp. 514-531.
Chen W, Guo N, Qi M, et al. Discovery, mechanism and metabolism studies of 2,3-difluorophenyl-linker-containing PARP1 inhibitors with enhanced in vivo efficacy for cancer therapy. Eur J Med Chem. 2017;138:514-531.
Chen, W., Guo, N., Qi, M., Dai, H., Hong, M., Guan, L., Huan, X., Song, S., He, J., Wang, Y., Xi, Y., Yang, X., Shen, Y., Su, Y., Sun, Y., Gao, Y., Chen, Y., Ding, J., Tang, Y., ... Li, J. (2017). Discovery, mechanism and metabolism studies of 2,3-difluorophenyl-linker-containing PARP1 inhibitors with enhanced in vivo efficacy for cancer therapy. European Journal of Medicinal Chemistry, 138, 514-531. https://doi.org/10.1016/j.ejmech.2017.06.053
Chen W, et al. Discovery, Mechanism and Metabolism Studies of 2,3-difluorophenyl-linker-containing PARP1 Inhibitors With Enhanced in Vivo Efficacy for Cancer Therapy. Eur J Med Chem. 2017 Sep 29;138:514-531. PubMed PMID: 28692916.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery, mechanism and metabolism studies of 2,3-difluorophenyl-linker-containing PARP1 inhibitors with enhanced in vivo efficacy for cancer therapy. AU - Chen,Wenhua, AU - Guo,Ne, AU - Qi,Minghui, AU - Dai,Haiying, AU - Hong,Minghuang, AU - Guan,Longfei, AU - Huan,Xiajuan, AU - Song,Shanshan, AU - He,Jinxue, AU - Wang,Yingqing, AU - Xi,Yong, AU - Yang,Xinying, AU - Shen,Yanyan, AU - Su,Yi, AU - Sun,Yiming, AU - Gao,Yinglei, AU - Chen,Yi, AU - Ding,Jian, AU - Tang,Yun, AU - Ren,Guobin, AU - Miao,Zehong, AU - Li,Jian, Y1 - 2017/06/27/ PY - 2017/04/23/received PY - 2017/05/30/revised PY - 2017/06/25/accepted PY - 2017/7/12/pubmed PY - 2017/10/3/medline PY - 2017/7/11/entrez KW - Antitumor drug KW - BRCA1/2 KW - Molecular docking KW - PARP inhibitors SP - 514 EP - 531 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 138 N2 - Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially breast and ovarian cancers, and tumor cell lines deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, with the help of molecular docking, we identified a novel series of 2,3-difluorophenyl-linker analogues (15-54) derived from olaparib (1) as PARP1 inhibitors. Lead optimization led to the identification of 47, which showed high selectivity and high potency against PARP1 enzyme (IC50 = 1.3 nM), V-C8 cells (IC50 = 0.003 nM), Capan-1 cells (IC50 = 7.1 nM) and MDA-MB-436 cells (IC50 = 0.2 nM). Compound 47 had more potent PARP1-DNA trapping and double-strand breaks (DSBs)-induction activities than 1 and induced G2/M arrest and caspase-dependent apoptosis. Compound 47 (50 mg/kg, 94.2%) had a more beneficial effect on tumor growth inhibition than 1 (100 mg/kg, 65.0%) in a BRCA1-mutated xenograft model and significantly inhibited tumor growth (40 mg/kg, 48.1%) in a BRCA2-mutated xenograft model, with no negative influence on the body weight of the mice. Collectively, these data demonstrated that 47 might be an excellent drug candidate for the treatment of cancer, especially for BRCA-deficient tumors. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/28692916/Discovery_mechanism_and_metabolism_studies_of_23_difluorophenyl_linker_containing_PARP1_inhibitors_with_enhanced_in_vivo_efficacy_for_cancer_therapy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(17)30507-X DB - PRIME DP - Unbound Medicine ER -