title: Inhibition of neuronal apoptosis by the cyclin-dependent kinase inhibitor GW8510: identification of 3' substituted indolones as a scaffold for the development of neuroprotective drugs.
abstract: Increasing evidence suggests that neuronal apoptosis is triggered by the inappropriate activation of cyclin-dependent kinases leading to an abortive re-entry of neurons into the cell cycle. Pharmacological inhibitors of cell-cycle progression may therefore have value in the treatment of neurodegenerative diseases in humans. GW8510 is a 3' substituted indolone that was developed recently as an inhibitor of cyclin-dependent kinase 2 (CDK2). We found that GW8510 inhibits the death of cerebellar granule neurons caused by switching them from high potassium (HK) medium to low potassium (LK) medium. Although GW8510 inhibits CDK2 and other CDKs when tested in in vitro biochemical assays, when used on cultured neurons it only inhibits CDK5, a cytoplasmic CDK that is not associated with cell-cycle progression. Treatment of cultured HEK293T cells with GW8510 does not inhibit cell-cycle progression, consistent with its inability to inhibit mitotic CDKs in intact cells. Neuroprotection by GW8510 is independent of Akt and MEK-ERK signaling. Furthermore, GW8510 does not block the LK-induced activation of Gsk3beta and, while inhibiting c-jun phosphorylation, does not inhibit the increase in c-jun expression observed in apoptotic neurons. We also examined the effectiveness of other 3' substituted indolone compounds to protect against neuronal apoptosis. We found that like GW8510, the VEGF Receptor 2 Kinase Inhibitors [3-(1H-pyrrol-2-ylmethylene)-1,3-dihydroindol-2-one], {(Z)-3-[2,4-Dimethyl-3-(ethoxycarbonyl)pyrrol-5-yl)methylidenyl]indol-2-one} and [(Z)-5-Bromo-3-(4,5,6,6-tetrahydro-1H-indol-2-ylmethylene)-1,3-dihydroindol-2-one], the Src family kinase inhibitor SU6656 and a commercially available inactive structural analog of an RNA-dependent protein kinase inhibitor 5-Chloro-3-(3,5-dichloro-4-hydroxybenzylidene)-1,3-dihydro-indol-2-one, are all neuroprotective when tested on LK-treated neurons. Along with our recent identification of the c-Raf inhibitor GW5074 (also a 3' substituted indolone) as a neuroprotective compound, our findings identify the 3' substituted indolone as a core structure for the designing of neuroprotective drugs that may be used to treat neurodegenerative diseases in humans.
authors.affiliation: Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, Texas 75083, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Johnson
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Nazanin
authors.initials: N
authors.lastname: Majdzadeh
authors.forename: Cindy
authors.initials: C
authors.lastname: Chavez
authors.forename: Paul C
authors.initials: PC
authors.lastname: Chin
authors.forename: Brad
authors.initials: B
authors.lastname: Morrison
authors.forename: Lulu
authors.initials: L
authors.lastname: Wang
authors.forename: Jane
authors.initials: J
authors.lastname: Park
authors.forename: Priti
authors.initials: P
authors.lastname: Chugh
authors.forename: Hsin-Mei
authors.initials: HM
authors.lastname: Chen
authors.forename: Santosh R
authors.initials: SR
authors.lastname: D'Mello
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: C500810:GW8510; D007211:Indoles; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D018844:Cyclin-Dependent Kinases