Discovery of a novel series of 4-quinolone JNK inhibitors

Gong, Leyi; Tan, Yun-Chou; Boice, Geneviève N.; Abbot, Sarah C.; McCaleb, Kristen L.; Iyer, Pravin S.; Zuo, Fengrong; Porto, Joseph Dal; Wong, Brian; Jin, Sue; Chang, Alice Y.W.; Tran, Patricia; Hsieh, Gary; Niu, Linghao; Shao, A.; Reuter, Deborah C.; Lukacs, C.M.; Kammlott, R.U.; Kuglstatter, A.; Goldstein, David

doi:10.1016/j.bmcl.2012.10.066

Cited by 17 publications

(15 citation statements)

References 21 publications

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“…4) was characterized by strong H-bonding between the oxygen atom of the amide group and Met111. It should be noted that Met111 is considered as an important residue for small molecule interactions with JNK [52, 53]. The calculated docking score for tryptanthrin-6-oxime was about 15 kcal/mol more negative than for tryptanthrin, which may explain the higher binding affinity of the oxime derivative.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, biological evaluation, and molecular modeling of 11H-indeno[1,2-b]quinoxalin-11-one derivatives and tryptanthrin-6-oxime as c-Jun N-terminal kinase inhibitors

Schepetkin

Khlebnikov

Potapov

et al. 2019

European Journal of Medicinal Chemistry

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c-Jun N-terminal kinases (JNKs) play a central role in many physiologic and pathologic processes. We synthesized novel 11H-indeno[1,2-b]quinoxalin-11-one oxime analogs and tryptanthrin-6-oxime (indolo(2,1-b)quinazoline-6,12-dion-6-oxime) and evaluated their effects on JNK activity. Several compounds exhibited sub-micromolar JNK binding affinity and were selective for JNK1/JNK3 versus JNK2.The most potent compounds were 10c (11H-indeno[1,2b]quinoxalin-11-one O-(O-ethylcarboxymethyl) oxime) and tryptanthrin-6-oxime, which had dissociation constants (Kd) for JNK1 and JNK3 of 22 and 76 nM and 150 and 275 nM, respectively. Molecular modeling suggested a mode of binding interaction at the JNK catalytic site and that the selected oxime derivatives were potentially competitive JNK inhibitors. JNK binding activity of the compounds correlated with their ability to inhibit lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) activation in human monocytic THP-1Blue cells and interleukin-6 (IL-6) production by human MonoMac-6 cells. Thus, oximes with indenoquinoxaline and tryptanthrin nuclei can serve as specific smallmolecule modulators for mechanistic studies of JNK, as well as potential leads for the development of anti-inflammatory drugs.

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Section: Resultsmentioning

confidence: 99%

Synthesis, biological evaluation, and molecular modeling of 11H-indeno[1,2-b]quinoxalin-11-one derivatives and tryptanthrin-6-oxime as c-Jun N-terminal kinase inhibitors

Schepetkin

Khlebnikov

Potapov

et al. 2019

European Journal of Medicinal Chemistry

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“…compound 58. 128 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 43 protein kinases than the JNKs were inhibited by more than 50% at a testing concentration of 10 µM (percent of competition for JNK1, JNK2 and JNK3 is 96, 98 and 99, respectively). Beside this outstanding selectivity, inhibitor 59 exhibited moderate solubility and clearance.…”

Section: Quinolones and Azaquinolonesmentioning

confidence: 97%

“…24). 128 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 42 JNK2 inhibitors, e.g. compound 58.…”

Section: Quinolones and Azaquinolonesmentioning

confidence: 99%

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Inhibitors of c-Jun N-Terminal Kinases: An Update

2014

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The c-Jun N-terminal kinases (JNKs) are serine/threonine kinases implicated in the pathogenesis of various diseases. Recent advances in the development of novel inhibitors of JNKs will be reviewed. Significant progress in the design of JNK inhibitors displaying selectivity versus other kinases has been achieved within the past 4 years. However, the development of isoform selective JNK inhibitors is still an open task.

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“…It has been suggested that c-Jun N-terminal kinases (JNK) play a role in VHL-independent degradation of HIF proteins ( 68 , 69 ). Gong et al ( 68 ) found that some quinolone-derived drugs bound strongly to the ATP binding pocket of JNK1. Zhang et al ( 69 ) suggested a PHD-VHL-independent mechanism of HIF-1α degradation involving chaperone proteins HSP90 and HSP70.…”

Section: Resultsmentioning

confidence: 99%

Nonantibiotic Effects of Fluoroquinolones in Mammalian Cells

Badal

Her

Maher

2015

Journal of Biological Chemistry

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Background: Fe(II)-dependent dioxygenases regulate epigenetic control, collagen maturation, and HIF degradation.Results: Iron chelation by fluoroquinolone antibiotics results in DNA and histone hypermethylation, suppression of collagen prolyl hydroxylation, and inhibition of HIF mRNA translation.Conclusion: Dioxygenase inhibition may explain renal toxicity and tendinopathy side effects of fluoroquinolones.Significance: This study suggests mechanisms for obscure fluoroquinolone-associated side effects and possible novel applications of these antibiotics as HIF antagonists.

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Discovery of a novel series of 4-quinolone JNK inhibitors

Cited by 17 publications

References 21 publications

Synthesis, biological evaluation, and molecular modeling of 11H-indeno[1,2-b]quinoxalin-11-one derivatives and tryptanthrin-6-oxime as c-Jun N-terminal kinase inhibitors

Synthesis, biological evaluation, and molecular modeling of 11H-indeno[1,2-b]quinoxalin-11-one derivatives and tryptanthrin-6-oxime as c-Jun N-terminal kinase inhibitors

Inhibitors of c-Jun N-Terminal Kinases: An Update

Nonantibiotic Effects of Fluoroquinolones in Mammalian Cells

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