title: Discovery of potent and selective covalent inhibitors of JNK.
abstract: The mitogen-activated kinases JNK1/2/3 are key enzymes in signaling modules that transduce and integrate extracellular stimuli into coordinated cellular response. Here, we report the discovery of irreversible inhibitors of JNK1/2/3. We describe two JNK3 cocrystal structures at 2.60 and 2.97 Å resolution that show the compounds form covalent bonds with a conserved cysteine residue. JNK-IN-8 is a selective JNK inhibitor that inhibits phosphorylation of c-Jun, a direct substrate of JNK, in cells exposed to submicromolar drug in a manner that depends on covalent modification of the conserved cysteine residue. Extensive biochemical, cellular, and pathway-based profiling establish the selectivity of JNK-IN-8 for JNK and suggests that the compound will be broadly useful as a pharmacological probe of JNK-dependent signal transduction. Potential lead compounds have also been identified for kinases, including IRAK1, PIK3C3, PIP4K2C, and PIP5K3.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Tinghu
authors.initials: T
authors.lastname: Zhang
authors.forename: Francisco
authors.initials: F
authors.lastname: Inesta-Vaquera
authors.forename: Mario
authors.initials: M
authors.lastname: Niepel
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhang
authors.forename: Scott B
authors.initials: SB
authors.lastname: Ficarro
authors.forename: Thomas
authors.initials: T
authors.lastname: Machleidt
authors.forename: Ting
authors.initials: T
authors.lastname: Xie
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Marto
authors.forename: NamDoo
authors.initials: N
authors.lastname: Kim
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.forename: John D
authors.initials: JD
authors.lastname: Laughlin
authors.forename: Hajeung
authors.initials: H
authors.lastname: Park
authors.forename: Philip V
authors.initials: PV
authors.lastname: LoGrasso
authors.forename: Matt
authors.initials: M
authors.lastname: Patricelli
authors.forename: Tyzoon K
authors.initials: TK
authors.lastname: Nomanbhoy
authors.forename: Peter K
authors.initials: PK
authors.lastname: Sorger
authors.forename: Dario R
authors.initials: DR
authors.lastname: Alessi
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary
chemical_list: D047428:Protein Kinase Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases