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Moustakim, Moses; Riedel, Kerstin; Schuller, Marion; Gehring, Andre P.; Monteiro, Octovia P.; Martin, Sarah P.; Fedorov, Oleg; Heer, Jag; Dixon, Darren J.; Elkins, Jonathan M.; Knapp, Stefan; Bracher, Franz; Brennan, Paul E. (2018): Discovery of a novel allosteric inhibitor scaffold for polyadenosine-diphosphate-ribose polymerase 14 (PARP14) macrodomain 2. In: Bioorganic & Medicinal Chemistry, Vol. 26, No. 11: pp. 2965-2972
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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) macro-domains (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.