Design and evaluation of 1,7-naphthyridones as novel KDM5 inhibitors

[Display omitted] Features from a high throughput screening (HTS) hit and a previously reported scaffold were combined to generate 1,7-naphthyridones as novel KDM5 enzyme inhibitors with nanomolar potencies. These molecules exhibited high selectivity over the related KDM4C and KDM2B isoforms. An X-r...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2016-09, Vol.26 (18), p.4492-4496
Hauptverfasser:	Labadie, Sharada S., Dragovich, Peter S., Cummings, Richard T., Deshmukh, Gauri, Gustafson, Amy, Han, Ning, Harmange, Jean-Christophe, Kiefer, James R., Li, Yue, Liang, Jun, Liederer, Bianca M., Liu, Yichin, Manieri, Wanda, Mao, Wiefeng, Murray, Lesley, Ortwine, Daniel F., Trojer, Patrick, VanderPorten, Erica, Vinogradova, Maia, Wen, Li
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Crystallography, X-Ray Dogs Drug Design Epigenetics Histone lysine demethylases Humans Jumonji Domain-Containing Histone Demethylases - antagonists & inhibitors KDM5 inhibitors Madin Darby Canine Kidney Cells Naphthyridines - chemistry Naphthyridines - pharmacology Nuclear Proteins - antagonists & inhibitors Repressor Proteins - antagonists & inhibitors Retinoblastoma-Binding Protein 2 - antagonists & inhibitors Structure-Activity Relationship
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Zusammenfassung:	[Display omitted] Features from a high throughput screening (HTS) hit and a previously reported scaffold were combined to generate 1,7-naphthyridones as novel KDM5 enzyme inhibitors with nanomolar potencies. These molecules exhibited high selectivity over the related KDM4C and KDM2B isoforms. An X-ray co-crystal structure of a representative molecule bound to KDM5A showed that these inhibitors are competitive with the co-substrate (2-oxoglutarate or 2-OG).
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2016.07.070