title: Inhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional Effects.
abstract: The mood stabilizer lithium, the first-line treatment for bipolar disorder, is hypothesized to exert its effects through direct inhibition of glycogen synthase kinase 3 (GSK3) and indirectly by increasing GSK3's inhibitory serine phosphorylation. GSK3 comprises two highly similar paralogs, GSK3α and GSK3β, which are key regulatory kinases in the canonical Wnt pathway. GSK3 stands as a nodal target within this pathway and is an attractive therapeutic target for multiple indications. Despite being an active field of research for the past 20 years, many GSK3 inhibitors demonstrate either poor to moderate selectivity versus the broader human kinome or physicochemical properties unsuitable for use in in vitro systems or in vivo models. A nonconventional analysis of data from a GSK3β inhibitor high-throughput screening campaign, which excluded known GSK3 inhibitor chemotypes, led to the discovery of a novel pyrazolo-tetrahydroquinolinone scaffold with unparalleled kinome-wide selectivity for the GSK3 kinases. Taking advantage of an uncommon tridentate interaction with the hinge region of GSK3, we developed highly selective and potent GSK3 inhibitors, BRD1652 and BRD0209, which demonstrated in vivo efficacy in a dopaminergic signaling paradigm modeling mood-related disorders. These new chemical probes open the way for exclusive analyses of the function of GSK3 kinases in multiple signaling pathways involved in many prevalent disorders.
authors.forename: Florence F
authors.initials: FF
authors.lastname: Wagner
authors.affiliation: Chemical Neurobiology Laboratory, Departments of Neurology & Psychiatry, Massachusetts General Hospital, Harvard Medical School , Boston, Massachusetts 02215, United States.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Bishop
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Gale
authors.forename: Xi
authors.initials: X
authors.lastname: Shi
authors.forename: Michelle
authors.initials: M
authors.lastname: Walk
authors.forename: Joshua
authors.initials: J
authors.lastname: Ketterman
authors.affiliation: Chemical Neurobiology Laboratory, Departments of Neurology & Psychiatry, Massachusetts General Hospital, Harvard Medical School , Boston, Massachusetts 02215, United States.
authors.forename: Debasis
authors.initials: D
authors.lastname: Patnaik
authors.forename: Doug
authors.initials: D
authors.lastname: Barker
authors.forename: Deepika
authors.initials: D
authors.lastname: Walpita
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Campbell
authors.forename: Shannon
authors.initials: S
authors.lastname: Nguyen
authors.forename: Michael
authors.initials: M
authors.lastname: Lewis
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital , Boston, Massachusetts 02215, United States.
authors.forename: Linda
authors.initials: L
authors.lastname: Ross
authors.forename: Michel
authors.initials: M
authors.lastname: Weïwer
authors.forename: W Frank
authors.initials: WF
authors.lastname: An
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Germain
authors.forename: Partha P
authors.initials: PP
authors.lastname: Nag
authors.forename: Shailesh
authors.initials: S
authors.lastname: Metkar
authors.forename: Taner
authors.initials: T
authors.lastname: Kaya
authors.forename: Sivaraman
authors.initials: S
authors.lastname: Dandapani
authors.forename: David E
authors.initials: DE
authors.lastname: Olson
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Barbe
authors.forename: Fanny
authors.initials: F
authors.lastname: Lazzaro
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Sacher
authors.forename: Jaime H
authors.initials: JH
authors.lastname: Cheah
authors.forename: David
authors.initials: D
authors.lastname: Fei
authors.forename: Jose
authors.initials: J
authors.lastname: Perez
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
authors.forename: Michelle
authors.initials: M
authors.lastname: Palmer
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital , Boston, Massachusetts 02215, United States.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Stegmaier
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.forename: Edward
authors.initials: E
authors.lastname: Scolnick
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Zhang
authors.affiliation: Chemical Neurobiology Laboratory, Departments of Neurology & Psychiatry, Massachusetts General Hospital, Harvard Medical School , Boston, Massachusetts 02215, United States.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.forename: Edward B
authors.initials: EB
authors.lastname: Holson
authors.forename: Jen Q
authors.initials: JQ
authors.lastname: Pan
mesh_terms: D000818:Animals; D015195:Drug Design; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D038362:Glycogen Synthase Kinase 3