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

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.

• Authors: Mukul R Jain, Jogeswar Mohapatra, Debdutta Bandhyopadhyay, Abhijit Chatterjee, Krishnarup Ghoshdastidar, Dinesh Patel, Ankit Patel, Hitesh Bhayani, Brijesh Kumar Srivastava, Sandeep A Shedage, Pravin Kadam, Rajesh Sundar, Harilal Patel, Poonam Giri, Prakash Patel, Laxmikant Gupta, Nuggehally R Srinivas, Pankaj R Patel, Ranjit C Desai
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 82 Issue 4 Pg. 635-647 (10 2018) ISSN: 1432-0843 [Electronic] Germany
• PMID: 30046848 (Publication Type: Journal Article)

Chemical References

• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases
• Tankyrases

Topics

• Animals
• Apoptosis (drug effects)
• Biological Availability
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colonic Neoplasms (drug therapy)
• DNA Damage (drug effects)
• Dogs
• Drug Monitoring (methods)
• Humans
• Mice
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Rats
• Rats, Wistar
• Tankyrases (antagonists & inhibitors)
• Treatment Outcome
• Xenograft Model Antitumor Assays