Aminopyridine-Based c-Jun N-Terminal Kinase Inhibitors with Cellular Activity and Minimal Cross-Kinase Activity

Szczepankiewicz, Bruce G.; Kosogof, Christi; Nelson, Lawrence J.; Liu, Gang; Liu, Bo; Zhao, Hongyu; Serby, Michael D.; Xin, Zhili; Liu, Mei; Gum, Rebecca J.; Haasch, Deanna L.; Wang, Sanyi; Clampit, Jill E.; Johnson, Eric F.; Lübben, Thomas; Stashko, Michael A.; Olejniczak, Edward T.; Sun, Chaohong; Dorwin, Sarah A.; Haskins, Kristi; Abad‐Zapatero, Celerino; Fry, Elizabeth H.; Hutchins, Charles W.; Sham, Hing L.; Rondinone, Cristina M.; Trevillyan, James M.

doi:10.1021/jm060199b

Cited by 135 publications

(112 citation statements)

References 51 publications

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“…Likewise, 12.5 ng/ml TRAIL induced apoptosis in 33 Ϯ 10% of Jurkat cells in the absence of SP600125 and 54 Ϯ 8% in the presence of SP600125 (n ϭ 3; p ϭ 0.03). Similar effects were observed with N-(4-amino-5-cyano-6-ethoxypyridin-2-yl)-2-(2,5-dimethoxy-phenyl) acetamide, 4 a structurally unrelated JNK inhibitor (67).…”

Section: Bcl-2 Family Trafficking During Trail-induced Apoptosissupporting

confidence: 66%

MCL-1 as a Buffer for Proapoptotic BCL-2 Family Members during TRAIL-induced Apoptosis

Meng

Lee

Dai

et al. 2007

Journal of Biological Chemistry

106

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Previous studies have suggested that Mcl-1, an antiapoptotic Bcl-2 homolog that does not exhibit appreciable affinity for the caspase 8-generated C-terminal Bid fragment (tBid), diminishes sensitivity to tumor necrosis factor-␣-related apoptosis-inducing ligand (TRAIL). This study was performed to determine the mechanism by which Mcl-1 confers TRAIL resistance and to evaluate methods for overcoming this resistance. Affinity purification/immunoblotting assays using K562 human leukemia cells, which con-

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Section: Bcl-2 Family Trafficking During Trail-induced Apoptosissupporting

confidence: 66%

MCL-1 as a Buffer for Proapoptotic BCL-2 Family Members during TRAIL-induced Apoptosis

Meng

Lee

Dai

et al. 2007

Journal of Biological Chemistry

106

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“…S1 in the supplemental material). In contrast, inhibition of JNK by either JI8 (63,77) or SP600125 (6) completely cancelled induction of ATF2 phosphorylation in response to leucine starvation. These results suggest that JNK rather than p38 or ERK is responsible for amino acid regulation of ATF2 phosphorylation.…”

Section: Resultsmentioning

confidence: 94%

Identification of a Novel Amino Acid Response Pathway Triggering ATF2 Phosphorylation in Mammals

Chaveroux

Jousse

Chérasse

et al. 2009

Molecular and Cellular Biology

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It has been well established that amino acid availability can control gene expression. Previous studies have shown that amino acid depletion induces transcription of the ATF3 (activation transcription factor 3) gene through an amino acid response element (AARE) located in its promoter. This event requires phosphorylation of activating transcription factor 2 (ATF2), a constitutive AARE-bound factor. To identify the signaling cascade leading to phosphorylation of ATF2 in response to amino acid starvation, we used an individual gene knockdown approach by small interfering RNA transfection. We identified the mitogen-activated protein kinase (MAPK) module MEKK1/MKK7/JNK2 as the pathway responsible for ATF2 phosphorylation on the threonine 69 (Thr69) and Thr71 residues. Then, we progressed backwards up the signal transduction pathway and showed that the GTPase Rac1/Cdc42 and the protein G␣12 control the MAPK module, ATF2 phosphorylation, and AARE-dependent transcription. Taken together, our data reveal a new signaling pathway activated by amino acid starvation leading to ATF2 phosphorylation and subsequently positively affecting the transcription of amino acid-regulated genes.

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“…To confirm that the effect of JNK downregulation was due to loss of JNK catalytic activity, 4T1-Luc cells were treated with increasing concentrations of three chemically distinct pan-JNK small-molecule inhibitors, SP600125 (28), JNK inhibitor VIII (29,30), and JNK-IN-8 (13). JNK inhibition was monitored by a decrease in Ser63 phosphorylation of the JNK downstream target c-Jun (Fig.…”

Section: Resultsmentioning

confidence: 99%

An In Vivo Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer

Ashenden

Weverwijk

Murugaesu

et al. 2017

Molecular Cancer Therapeutics

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Chemotherapy remains the mainstay of treatment for advanced breast cancer; however, resistance is an inevitable event for the majority of patients with metastatic disease. Moreover, there is little information available to guide stratification of firstline chemotherapy, crucial given the common development of multidrug resistance. Here, we describe an in vivo screen to interrogate the response to anthracycline-based chemotherapy in a syngeneic metastatic breast cancer model and identify JNK signaling as a key modulator of chemotherapy response. Combining in vitro and in vivo functional analyses, we demonstrate that JNK inhibition both promotes tumor cell cytostasis and blocks activation of the proapoptotic protein Bax, thereby antagonizing chemotherapy-mediated cytotoxicity. To investigate the clinical relevance of this dual role of JNK signaling, we developed a proliferation-independent JNK activity signature and demonstrate high JNK activity to be enriched in triple-negative and basal-like breast cancer subtypes. Consistent with the dual role of JNK signaling in vitro, high-level JNK pathway activation in triplenegative breast cancers is associated both with poor patient outcome in the absence of chemotherapy treatment and, in neoadjuvant clinical studies, is predictive of enhanced chemotherapy response. These data highlight the potential of monitoring JNK activity as early biomarker of response to chemotherapy and emphasize the importance of rational treatment regimes, particularly when combining cytostatic and chemotherapeutic agents.

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Aminopyridine-Based c-Jun N-Terminal Kinase Inhibitors with Cellular Activity and Minimal Cross-Kinase Activity

Cited by 135 publications

References 51 publications

MCL-1 as a Buffer for Proapoptotic BCL-2 Family Members during TRAIL-induced Apoptosis

MCL-1 as a Buffer for Proapoptotic BCL-2 Family Members during TRAIL-induced Apoptosis

Identification of a Novel Amino Acid Response Pathway Triggering ATF2 Phosphorylation in Mammals

An In Vivo Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer

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