Discovery of a novel allosteric inhibitor scaffold for polyadenosine-diphosphate-ribose polymerase 14 (PARP14) macrodomain 2

Moses Moustakim; Kerstin Riedel; Marion Schuller; Andrè P Gehring; Octovia P Monteiro; Sarah P Martin; Oleg Fedorov; Jag Heer; Darren J Dixon; Jonathan M Elkins; Stefan Knapp; Franz Bracher; Paul E Brennan

doi:10.1016/j.bmc.2018.03.020

Discovery of a novel allosteric inhibitor scaffold for polyadenosine-diphosphate-ribose polymerase 14 (PARP14) macrodomain 2

Bioorg Med Chem. 2018 Jul 15;26(11):2965-2972. doi: 10.1016/j.bmc.2018.03.020. Epub 2018 Mar 12.

Authors

Affiliations

¹ Structural 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.
² Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians University, Munich 81377, Germany.
³ Structural 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.
⁴ Charles River, Chesterford Research Park, CB10 1XL, UK.
⁵ UCB Pharma Ltd, Slough SL1 3WE, UK.
⁶ Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.
⁷ Structural Genomics Consortium, University of Oxford, ORCRB, Old Road Campus, Headington, Oxford, Oxfordshire OX3 7DQ, UK; Structural Genomics Consortium, Universidade Estadual de Campinas, Cidade Universitária Zeferino Vaz, Campinas, SP 13083-886, Brazil.
⁸ Johann Wolfgang Goethe-University, Institute for PharmaceuticalChemistry and Buchmann Institute for Life Sciences, Frankfurt am Main 60438, Germany; German Cancer Centre (DKFZ) and DKTK site Frankfurt/Mainz, 60590, Germany.
⁹ Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians University, Munich 81377, Germany. Electronic address: franz.bracher@cup.uni-muenchen.de.
¹⁰ Structural 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. Electronic address: paul.brennan@sgc.ox.ac.uk.

Abstract

The polyadenosine-diphosphate-ribose polymerase 14 (PARP14) has been implicated in DNA damage response pathways for homologous recombination. PARP14 contains three (ADP ribose binding) macrodomains (MD) whose exact contribution to overall PARP14 function in pathology remains unclear. A medium throughput screen led to the identification of N-(2(-9H-carbazol-1-yl)phenyl)acetamide (GeA-69, 1) as a novel allosteric PARP14 MD2 (second MD of PARP14) inhibitor. We herein report medicinal chemistry around this novel chemotype to afford a sub-micromolar PARP14 MD2 inhibitor. This chemical series provides a novel starting point for further development of PARP14 chemical probes.

Keywords: Inhibitor Design; Macrodomain; PARP; Poly-ADP ribsose.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation
Carbazoles / chemistry
Cysteine Endopeptidases / chemistry*
Drug Discovery*
Humans
Inhibitory Concentration 50
Models, Biological
Molecular Docking Simulation
Molecular Structure
Poly(ADP-ribose) Polymerase Inhibitors / chemical synthesis*
Poly(ADP-ribose) Polymerase Inhibitors / chemistry
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
Poly(ADP-ribose) Polymerases / chemistry*
Poly(ADP-ribose) Polymerases / drug effects
Structure-Activity Relationship

Substances

Carbazoles
Poly(ADP-ribose) Polymerase Inhibitors
Poly(ADP-ribose) Polymerases
Cysteine Endopeptidases
macrodontain-I protein, Pseudananas macrodontes

Abstract

Publication types

MeSH terms

Substances

Grants and funding