title: Poly (ADP-ribose) polymerases inhibitor, Zj6413, as a potential therapeutic agent against breast cancer.
abstract: Poly (ADP-ribose) polymerases (PARPs) facilitate repairing of cancer cell DNA damage as a mean to promote cancer proliferation and metastasis. Inhibitors of PARPs which interfering DNA repair, in context of defects in other DNA repair mechanisms, can thus be potentially exploited to inhibit or even kill cancer cells. However, nondiscriminatory inhibition of PARPs, such as PARP2, may lead to undesired consequences. Here, we demonstrated the design and development of the Zj6413 as a potent and selective PARP1 catalytic inhibitor. It trapped PARP1/2 at damaged sites of DNA. As expected, the Zj6413 showed notable anti-tumor activity against breast cancer gene (BRCA) deficient triple negative breast cancers (TNBCs). Zj6413 treated breast cancers (BCs) showed an elevated level of DNA damage evidenced by the accumulation of γ-H2AX foci and DNA damaged related proteins. Zj6413 also induced G2/M arrest and cell death in the MX-1, MDA-MB-453 BC cells, exerted chemo-sensitizing effect on BRCA proficient cancer cells and potentiated Temozolomide (TMZ)'s cytotoxicity in MX-1 xenograft tumors mice. In conclusion, our study provided evidence that a new PARP inhibitor strongly inhibited the catalytic activity of PARPs, trapped them on nicked DNA and damaged the cancer cells, eventually inhibiting the growth of breast tumor cells in vitro and in vivo.
authors.affiliation: State Key laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 XianNongTan Street, Beijing 100050, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: State Key laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 XianNongTan Street, Beijing 100050, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Ji
authors.affiliation: State Key laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 XianNongTan Street, Beijing 100050, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: State Key laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 XianNongTan Street, Beijing 100050, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.affiliation: State Key laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 XianNongTan Street, Beijing 100050, China.
authors.forename: Nina
authors.initials: N
authors.lastname: Xue
authors.affiliation: State Key laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 XianNongTan Street, Beijing 100050, China.
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 XianNongTan Street, Beijing 100050, China. Electronic address: blxu@imm.ac.cn.
authors.forename: Bailing
authors.initials: B
authors.lastname: Xu
authors.affiliation: State Key laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 XianNongTan Street, Beijing 100050, China. Electronic address: chxg@imm.ac.cn.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003606:Dacarbazine / Q000009:adverse effects / Q000819:agonists / Q000031:analogs & derivatives / Q000627:therapeutic use; D054313:Drug Agonism; D015195:Drug Design; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008819:Mice, Nude; D017646:Organosilicon Compounds / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D052999:Quinazolinones / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D000077204:Temozolomide; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D017646:Organosilicon Compounds; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D052999:Quinazolinones; D011994:Recombinant Proteins; C000609887:Zj6413; D003606:Dacarbazine; C499320:PARP1 protein, human; C483041:PARP2 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D000077204:Temozolomide
keywords: BRCA deficient; Breast cancer; DNA damage repair; PARP inhibitor; Zj-6413