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Identification and preclinical characterization of a novel and potent poly (ADP-ribose) polymerase (PARP) inhibitor ZYTP1

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

ZYTP1 is a novel PARP inhibitor that showed potential for development as a treatment for various solid tumors.

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Authors and Affiliations

  1. Department of Pharmacology, Zydus Research Centre, Moraiya, Ahmadabad, Gujarat, India

    Mukul R. Jain, Jogeswar Mohapatra, Abhijit Chatterjee & Dinesh Patel

  2. Department of Medicinal Chemistry, Zydus Research Centre, Moraiya, Ahmadabad, Gujarat, India

    Brijesh Kumar Srivastava, Sandeep A. Shedage, Pravin Kadam & Ranjit C. Desai

  3. Department of Cell Biology, Zydus Research Centre, Moraiya, Ahmadabad, Gujarat, India

    Debdutta Bandhyopadhyay, Krishnarup Ghoshdastidar, Ankit Patel & Hitesh Bhayani

  4. Department of Toxicology, Zydus Research Centre, Moraiya, Ahmadabad, Gujarat, India

    Rajesh Sundar

  5. Department of Pharmacokinetics, Zydus Research Centre, Moraiya, Ahmadabad, Gujarat, India

    Harilal Patel, Poonam Giri, Prakash Patel, Laxmikant Gupta & Nuggehally R. Srinivas

  6. Zydus Research Centre, Cadila Healthcare Ltd, Satellite cross road, Ahmadabad, Gujarat, India

    Pankaj R. Patel

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  1. Mukul R. Jain
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Correspondence to Abhijit Chatterjee.

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Conflict of interest

The authors acknowledge that this work was supported by Zydus Research Centre, Ahmedabad, India and declare that there were no potential conflicts of interest.

Ethical approval

The current work involves the use of animals. All animal care and experimental procedures were in compliance with the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals as stated by the National Institutes of Health and were approved by the Institutional Animal Ethics Committee.

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Jain, M.R., Mohapatra, J., Bandhyopadhyay, D. et al. Identification and preclinical characterization of a novel and potent poly (ADP-ribose) polymerase (PARP) inhibitor ZYTP1. Cancer Chemother Pharmacol 82, 635–647 (2018). https://doi.org/10.1007/s00280-018-3653-1

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