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Discovery of a novel allosteric inhibitor scaffold for polyadenosine-diphosphate-ribose polymerase 14 (PARP14)

Moses Moustakim1, Kerstin Riedel2, Marion Schuller3

  • 1Structural Genomics Consortium, University of Oxford, ORCRB, Old Road Campus, Headington, Oxford, Oxfordshire OX3 7DQ, UK; Target Discovery Institute, University of Oxford, NDM Research Building, Old Road Campus, Headington, Oxford, Oxfordshire OX3 7FZ, UK; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.

Bioorganic & Medicinal Chemistry
|March 24, 2018
PubMed

Insights

Scientists identified a novel inhibitor targeting the PARP14 enzyme

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Polyadenosine-diphosphate-ribose polymerase 14 (PARP14) is involved in DNA repair.
  • PARP14 has three macrodomains (MD) with unclear roles in disease.
  • Understanding PARP14 function is crucial for therapeutic development.

Purpose of the Study:

  • To identify and develop novel inhibitors of PARP14.
  • To investigate the role of PARP14 macrodomains in cellular processes.
  • To create chemical probes for studying PARP14 in pathology.

Main Methods:

  • High-throughput screening to identify initial hits.
  • Medicinal chemistry optimization of lead compounds.
  • Biochemical assays to confirm enzyme inhibition.

Main Results:

  • Identified N-(2(-9H-carbazol-1-yl)phenyl)acetamide (GeA-69) as a PARP14 inhibitor.
  • Developed a novel chemotype with sub-micromolar potency against PARP14 MD2.
  • Established a new series of PARP14 inhibitors for further research.

Conclusions:

  • GeA-69 is a potent allosteric inhibitor of PARP14 MD2.
  • This chemical series offers a promising starting point for developing PARP14-targeted therapeutics.
  • Further research can utilize these inhibitors as chemical probes to explore PARP14 functions.
Keywords:
Inhibitor DesignMacrodomainPARPPoly-ADP ribsose

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