Discovery of 2-(5-nitrothiazol-2-ylthio)benzo[d]thiazoles as novel c-Jun N-terminal kinase inhibitors

Bioorganic and Medicinal Chemistry

Volumn 17, Issue 7, 2009, Pages 2712-2717

  De, Surya K ^a   Chen, Li Hsing ^a   Stebbins, John L ^a   Machleidt, Thomas ^b   Riel Mehan, Megan ^a   Dahl, Russell ^a   Chen, Vida ^a   Yuan, Hongbin ^a   Barile, Elisa ^a   Emdadi, Aras ^a   Murphy, Ria ^a   Pellecchia, Maurizio ^a  

^a BURNHAM INSTITUTE   (United States)

^b INVITROGEN CORPORATION   (United States)

Author keywords

Allosteric kinase inbhibitors; DJNKI; JIP1; JNK1; JNK2

Indexed keywords

2 (5 NITROTHIAZOL 2 YLTHIO)BENZO[D]THIAZOLE DERIVATIVE; BENZIMIDAZOLE DERIVATIVE; BENZOTHIAZOLE DERIVATIVE; BENZOXAZOLE DERIVATIVE; MITOGEN ACTIVATED PROTEIN KINASE P38; STRESS ACTIVATED PROTEIN KINASE INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL REACTION; CONCENTRATION RESPONSE; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; STRUCTURE ACTIVITY RELATION;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; ALLOSTERIC REGULATION; BENZOTHIAZOLES; COMPUTER SIMULATION; DRUG DISCOVERY; JNK MITOGEN-ACTIVATED PROTEIN KINASES; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PEPTIDE FRAGMENTS; PROTEIN KINASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 62949201723     PISSN: 09680896     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmc.2009.02.046     Document Type: Article

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32. ®, supplemented with 1% charcoal/dextran-treated FBS, 100 U/mL penicillin and 100 μg/mL streptomycin, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, 25 mM HEPES pH 7.3, and lacking phenol red). After overnight incubation, cells were pretreated for 60 min with compound (indicated concentration) followed by 30 min of stimulation with 2 ng/mL of TNF-alpha which stimulates both JNK and p38. The medium was then removed by aspiration and the cells were lysed by adding 20 μl of lysis buffer (20 mM TRIS-HCl pH 7.6, 5 mM EDTA, 1% NP-40 substitute, 5 mM NaF, 150 mM NaCl, 1:100 protease and phosphatase inhibitor mix, SIGMA P8340 and P2850, respectively). The lysis buffer included 2 nM of the terbium labeled anti-pc-Jun (pSer73) detection antibodies (Invitrogen). After allowing the assay to equilibrate for 1 h at room temperature, TR-FRET emission ratios were determined on a BMG Pherastar fluorescence plate reader (excitation at 340 nm, emission 520 nm and 490 nm; 100 μs lag time, 200 μs integration time, emission ratio = Em520/Em 490).