title: GSK114: A selective inhibitor for elucidating the biological role of TNNI3K.
abstract: A series of selective TNNI3K inhibitors were developed by modifying the hinge-binding heterocycle of a previously reported dual TNNI3K/B-Raf inhibitor. The resulting quinazoline-containing compounds exhibit a large preference (up to 250-fold) for binding to TNNI3K versus B-Raf, are useful probes for elucidating the biological pathways associated with TNNI3K, and are leads for discovering novel cardiac medicines. GSK114 emerged as a leading inhibitor, displaying significant bias (40-fold) for TNNI3K over B-Raf, exceptional broad spectrum kinase selectivity, and adequate oral exposure to enable its use in cellular and in vivo studies.
authors.affiliation: Heart Failure DPU, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA. Electronic address: brian.2.lawhorn@gsk.com.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Lawhorn
authors.affiliation: Heart Failure DPU, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Philp
authors.affiliation: Platform Sciences and Technology, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Graves
authors.affiliation: Platform Sciences and Technology, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Shewchuk
authors.affiliation: Heart Failure DPU, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Holt
authors.affiliation: Heart Failure DPU, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gatto
authors.affiliation: Heart Failure DPU, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA.
authors.forename: Lara S
authors.initials: LS
authors.lastname: Kallander
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000621335:GSK114; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D013449:Sulfonamides; D017346:Protein Serine-Threonine Kinases; C481078:TNNI3K protein, human; D020930:MAP Kinase Kinase Kinases
keywords: B-Raf; Kinase selectivity; Quinazoline; Substituent effects; TNNI3K