Design and synthesis of potent inhibitors of the mono(ADP-ribosyl)transferase, PARP14

[Display omitted] A series of (Z)-4-(3-carbamoylphenylamino)-4-oxobut-2-enyl amides were synthesized and tested for their ability to inhibit the mono-(ADP-ribosyl)transferase, PARP14 (a.k.a. BAL-2; ARTD-8). Two synthetic routes were established for this series and several compounds were identified a...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2017-07, Vol.27 (13), p.2907-2911
Hauptverfasser:	Upton, Kristen, Meyers, Matthew, Thorsell, Ann-Gerd, Karlberg, Tobias, Holechek, Jacob, Lease, Robert, Schey, Garrett, Wolf, Emily, Lucente, Adrianna, Schüler, Herwig, Ferraris, Dana
Format:	Artikel
Sprache:	eng
Schlagworte:	ARTD-8 Dose-Response Relationship, Drug Drug Design Humans Models, Molecular Molecular Structure Mono(ADP-ribosyl) transferase PARP PARP14 Poly(ADP-ribose) Polymerase Inhibitors - chemistry Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Poly(ADP-ribose) Polymerases - metabolism Structure-Activity Relationship
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Zusammenfassung:	[Display omitted] A series of (Z)-4-(3-carbamoylphenylamino)-4-oxobut-2-enyl amides were synthesized and tested for their ability to inhibit the mono-(ADP-ribosyl)transferase, PARP14 (a.k.a. BAL-2; ARTD-8). Two synthetic routes were established for this series and several compounds were identified as sub-micromolar inhibitors of PARP14, the most potent of which was compound 4t, IC50=160nM. Furthermore, profiling other members of this series identified compounds with >20-fold selectivity over PARP5a/TNKS1, and modest selectivity over PARP10, a closely related mono-(ADP-ribosyl)transferase.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2017.04.089