title: Design and evaluation of 1,7-naphthyridones as novel KDM5 inhibitors.
abstract: 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).
authors: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Sharada S
authors: SS
authors: Labadie
authors: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Peter S
authors: PS
authors: Dragovich
authors: Constellation Pharmaceuticals Inc., 215 First Street, Suite 200, Cambridge, MA 02142, USA.
authors: Richard T
authors: RT
authors: Cummings
authors: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Gauri
authors: G
authors: Deshmukh
authors: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Amy
authors: A
authors: Gustafson
authors: Wuxi Apptec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors: Ning
authors: N
authors: Han
authors: Constellation Pharmaceuticals Inc., 215 First Street, Suite 200, Cambridge, MA 02142, USA.
authors: Jean-Christophe
authors: JC
authors: Harmange
authors: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: James R
authors: JR
authors: Kiefer
authors: Wuxi Apptec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors: Yue
authors: Y
authors: Li
authors: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Jun
authors: J
authors: Liang
authors: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Bianca M
authors: BM
authors: Liederer
authors: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Yichin
authors: Y
authors: Liu
authors: Constellation Pharmaceuticals Inc., 215 First Street, Suite 200, Cambridge, MA 02142, USA.
authors: Wanda
authors: W
authors: Manieri
authors: Wuxi Apptec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors: Wiefeng
authors: W
authors: Mao
authors: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Lesley
authors: L
authors: Murray
authors: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Daniel F
authors: DF
authors: Ortwine
authors: Constellation Pharmaceuticals Inc., 215 First Street, Suite 200, Cambridge, MA 02142, USA.
authors: Patrick
authors: P
authors: Trojer
authors: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Erica
authors: E
authors: VanderPorten
authors: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Maia
authors: M
authors: Vinogradova
authors: Wuxi Apptec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors: Li
authors: L
authors: Wen
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors*; D061985:Madin Darby Canine Kidney Cells; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D056485:Retinoblastoma-Binding Protein 2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D009287:Naphthyridines; D009687:Nuclear Proteins; D012097:Repressor Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C070050:KDM5A protein, human; C119611:KDM5B protein, human; D056485:Retinoblastoma-Binding Protein 2
keywords: Epigenetics; Histone lysine demethylases; KDM5 inhibitors