Identification and preclinical characterization of a novel and potent poly (ADP-ribose) polymerase (PARP) inhibitor ZYTP1
| Autor: | Jogeswar Mohapatra, Sandeep A. Shedage, Poonam Giri, Pravin Kadam, Ranjit C. Desai, Krishnarup Ghoshdastidar, Harilal Patel, Hitesh Bhayani, Brijesh Kumar Srivastava, Nuggehally R. Srinivas, Ankit Patel, Debdutta Bandhyopadhyay, Prakash Patel, Abhijit Chatterjee, Rajesh Sundar, Mukul R. Jain, Laxmikant Gupta, Pankaj R. Patel, Dinesh Patel |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research DNA damage Poly ADP ribose polymerase Biological Availability Apoptosis Breast Neoplasms Poly(ADP-ribose) Polymerase Inhibitors Pharmacology Toxicology Mice 03 medical and health sciences Dogs 0302 clinical medicine PARP1 In vivo Cell Line Tumor Animals Humans Pharmacology (medical) Rats Wistar IC50 Cell Proliferation Tankyrases Chemistry Xenograft Model Antitumor Assays In vitro Rats Treatment Outcome 030104 developmental biology Cell killing Oncology 030220 oncology & carcinogenesis Colonic Neoplasms PARP inhibitor Drug Monitoring Poly(ADP-ribose) Polymerases DNA Damage |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 82:635-647 |
| ISSN: | 1432-0843 0344-5704 |
| DOI: | 10.1007/s00280-018-3653-1 |
| Popis: | Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in the detection and repair of DNA damage. Studies have shown that inhibition of PARP and Tankyrase (TNKS) has significant antitumor effect in several types of cancers including BRCA-negative breast cancers. Identification of ZYTP1, a novel PARP inhibitor, through a battery of in vitro assays and in vivo studies. PARP and TNKS inhibitory activity of ZYTP1 was assessed in cell-free kinase assay. In vitro cell killing potency of ZYTP1 was tested in a panel of cell lines including BRCA-negative cells. ZYTP1 was also tested in xenograft models in combination with temozolomide (TMZ). The pharmacokinetic profile of ZYTP1 was determined in rodent and non-rodent preclinical species. Safety of ZYTP1 was assessed in Wistar rats and Beagle dogs upon repeated dosing. ZYTP1 inhibited PARP1, PARP2, Tankyrase-1 and Tankyrase-2 with IC50 of 5.4, 0.7, 133.3 and 289.8 nM, respectively, and additionally trapped PARP1 onto damaged DNA. It also potentiated MMS-mediated killing of different cancer cell lines. Compound demonstrated good Caco-2 cell permeability. The oral bioavailability of ZYTP1 in mice, rats and dogs ranged between 40 and 79% and demonstrated efficacy in colon cancer xenograft model at a dose of 1–10 mg/kg in combination with TMZ. In a 28-day repeat dosing, oral toxicity study in rats, it was found to show > 10× safety margin. ZYTP1 is a novel PARP inhibitor that showed potential for development as a treatment for various solid tumors. |
| Databáze: | OpenAIRE |
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