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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.

Original publication

DOI

10.1016/j.bmc.2018.03.020

Type

Journal article

Journal

Bioorg Med Chem

Publication Date

15/07/2018

Volume

26

Pages

2965 - 2972

Keywords

Inhibitor Design, Macrodomain, PARP, Poly-ADP ribsose, Allosteric Regulation, Carbazoles, Cysteine Endopeptidases, Drug Discovery, Humans, Inhibitory Concentration 50, Models, Biological, Molecular Docking Simulation, Molecular Structure, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, Structure-Activity Relationship