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

Mukul R Jain1, Jogeswar Mohapatra1, Debdutta Bandhyopadhyay2

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

Cancer Chemotherapy and Pharmacology
|July 27, 2018
PubMed
Abstract

Insights

ZYTP1 is a novel Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor demonstrating significant antitumor potential. This PARP inhibitor effectively targets cancer cells and shows promise for treating various solid tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Poly(ADP-ribose) polymerase-1 (PARP-1) is crucial for DNA damage repair.
  • Inhibiting PARP and Tankyrase (TNKS) shows antitumor effects, particularly in BRCA-negative cancers.

Purpose of the Study:

  • To identify and characterize ZYTP1, a novel inhibitor of PARP and TNKS.
  • To evaluate the preclinical efficacy and safety of ZYTP1 as a potential cancer therapeutic.

Main Methods:

  • ZYTP1's inhibitory activity against PARP and TNKS was assessed in vitro.
  • Anticancer potency was tested in various cell lines, including BRCA-negative cells.
  • Efficacy was evaluated in xenograft models, and pharmacokinetic and safety profiles were determined.

Main Results:

  • ZYTP1 inhibited PARP1, PARP2, Tankyrase-1, and Tankyrase-2 with nanomolar IC50 values.
  • The compound demonstrated good cell permeability and oral bioavailability (40-79%) in preclinical species.
  • ZYTP1 showed efficacy in a colon cancer xenograft model when combined with temozolomide (TMZ) and exhibited a significant safety margin.

Conclusions:

  • ZYTP1 is a novel PARP inhibitor with potent inhibitory activity.
  • The compound demonstrates promising preclinical efficacy and a favorable safety profile.
  • ZYTP1 holds potential for development as a treatment for various solid tumors.
Keywords:
PARPSolid tumorTankyraseZYTP1

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