Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor

Krenitsky, Veronique Plantevin; Nadolny, Lisa; Delgado, Mercedes; Ayala, Leticia; Clareen, Steven S.; Hilgraf, Robert; Albers, Ronald; Hegde, Sayee G.; D'Sidocky, N.; Sapienza, John; Wright, Jonathan; McCarrick, Meg; Bahmanyar, Sogole; Chamberlain, Philip P.; Delker, S.L.; Muir, Jeff; Giegel, David A.; Xu, Li; Celeridad, Maria; Lachowitzer, Jeff; Bennett, Brydon L.; Moghaddam, Mehran F.; Khatsenko, Oleg G.; Katz, Jason D.; Fan, R.; Bai, April; Tang, Yang; Shirley, Michael A.; Benish, Brent; Bodine, T.; Blease, Kate; Raymon, Heather K.; Cathers, Brian E.; Satoh, Yoshitaka

doi:10.1016/j.bmcl.2011.12.027

Cited by 90 publications

(35 citation statements)

References 19 publications

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“…We now show that functional p38 signaling in pancreatic cancer is a predictive marker of outcome in resected pancreatic cancer. This is consistent with the findings by Koizumi et al who noted the necessity of p38 activity for gemcitabine-induced toxicity of pancreatic cancer cells (48), and that JNK inhibition suppressed pancreatic cancer cell growth in both in vitro assays and in a genetically engineered mouse model of pancreatic cancer (49), lending support to in human studies of JNK inhibition in the adjuvant setting and potentially in patients receiving first line therapy for newly diagnosed advanced stage disease as well (50). …”

Section: Discussionsupporting

confidence: 91%

Functional p38 MAPK Identified by Biomarker Profiling of Pancreatic Cancer Restrains Growth through JNK Inhibition and Correlates with Improved Survival

Zhong

Naito

Cope

et al. 2014

Clinical Cancer Research

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Purpose Numerous biomarkers for pancreatic cancer have been reported. We determined the extent to which such biomarkers are expressed throughout metastatic progression, including those that effectively predict biologic behavior. Experimental Design Biomarker profiling was performed for 35 oncoproteins in matched primary and metastatic pancreatic cancer tissues from 36 rapid autopsy patients. Proteins of significance were validated by immunolabeling in an independent sample set, and functional studies were performed in vitro and in vivo. Results Most biomarkers were similarly expressed or lost in expression in most samples analyzed, and the matched primary and metastases from a specific patient were most similar to each other than to other patients. However, a subset of proteins showed extensive inter-patient heterogeneity one of which was p38 MAPK. Strong positive pp38 MAPK immunolabeling was significantly correlated with improved post-resection survival by multivariate analysis (median overall survival 27.9 months, p=0.041). In pancreatic cancer cells, inhibition of functional p38 by SB202190 increased cell proliferation in vitro in both low-serum and low-oxygen conditions. High functional p38 activity in vitro corresponded to lower levels of pJNK protein expression, and p38 inhibition resulted in increased pJNK and pMKK7 by Western blot. Moreover, JNK inhibition by SP600125 or MKK7 siRNA knockdown antagonized the effects of p38 inhibition by SB202190. In vivo, SP600125 significantly decreased growth rates of xenografts with high p38 activity compared to those without p38 expression. Conclusions Functional p38 MAPK activity contributes to overall survival through JNK signaling, thus providing a rationale for JNK inhibition in pancreatic cancer management.

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Section: Discussionsupporting

confidence: 91%

Functional p38 MAPK Identified by Biomarker Profiling of Pancreatic Cancer Restrains Growth through JNK Inhibition and Correlates with Improved Survival

Zhong

Naito

Cope

et al. 2014

Clinical Cancer Research

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“…Immunoblotting confirmed enhanced JNK phosphorylation in XBP1Δ splenic cDC1s (Suppl Fig 5D). To explore whether JNK was mediating cell death of XBP1 deficient lung cDC1s, we treated the XBP1ΔDC mice with CC-930, a novel specific inhibitor of JNK phosphorylation ( 38 and validated in Suppl Fig 5E). As noticed in Fig 6E and F, CC-930 treatment was unable to rescue lung cDC1s and migratory counterparts in the MedLN.…”

Section: Resultsmentioning

confidence: 99%

Regulated IRE1-dependent mRNA decay sets the threshold for dendritic cell survival

et al. 2017

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Summary The IRE1/XBP1 signaling pathway is part of a cellular program that protects from endoplasmic reticulum (ER) stress, but also controls development and survival of immune cells. Loss of XBP1 in splenic type 1 conventional dendritic cells (cDC1s) results in phenotypic and functional alterations without affecting cell survival. However, in mucosal cDC1s, loss of XBP1 impaired survival in a tissue specific manner - while lung cDC1s die, intestinal cDC1s survive. This was not caused by differential activation of ER stress cell death regulators CHOP or JNK. Rather, cell fate was determined by a differential ability to shut down protein synthesis via a protective ATF4-dependent integrated stress response. In addition, regulated IRE1 dependent mRNA decay (RIDD) occurred mainly in intestinal cDC1s, and compound deficiency of IRE1 endonuclease led to cDC1 loss also in the intestine. Thus, mucosal DCs differentially mount ATF4 and IRE1 dependent adaptive mechanisms to survive in the face of ER stress.

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“…Follow-up studies determined IC 50 values of 480 nM (MAPK2) and 379 nM (EGFR). The IC 50 values of JNK 1, 2, and 3 isomers were 52 nM, 5 nM and 5 nM, respectively 19. Dermal fibroblasts were incubated with CC-930 at concentrations from 0.1 to 10 µM for 24 h. For controls, fibroblasts were incubated with the solvent dimethyl sulphoxide in the same concentrations.…”

Section: Methodsmentioning

confidence: 99%

Jun N-terminal kinase as a potential molecular target for prevention and treatment of dermal fibrosis

et al. 2012

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ObjectivesThe hallmark of systemic sclerosis (SSc) is the accumulation of extracellular matrix proteins by pathologically activated fibroblasts. This study analysed the antifibrotic effects of the selective c-Jun N-terminal kinase (JNK) inhibitor, CC-930, which recently entered first clinical trials as a novel antifibrotic approach.MethodsPhosphorylated c-Jun was detected by western blot and immunohistochemistry. The model of bleomycin-induced dermal fibrosis and the tight skin 1 (TSK1) mouse model were used to investigate the effects of CC-930 on the prevention of experimental fibrosis. The potential of CC-930 to induce regression of fibrosis was assessed in a modified model of established fibrosis.ResultsTransforming growth factor beta (TGFβ) and platelet-derived growth factor (PDGF) activate JNK and stimulate the phosphorylation of its downstream target c-Jun. Incubation with CC-930 prevented the phosphorylation of c-Jun and reduced the stimulatory levels of these cytokines on the release of collagen. Inhibition of JNK prevented dermal thickening, myofibroblast differentiation and the accumulation of collagen in a dose-dependent manner in mice challenged with bleomycin and in TSK1 mice. In addition to the prevention of fibrosis, treatment with pharmacologically relevant doses of CC-930 also induced regression of established experimental fibrosis.ConclusionsThese data identify JNK as a downstream mediator of the pro-fibrotic effects of of TGFβ and PDGF in SSc fibroblasts. Selective inhibition of JNK by CC-930 exerted potent antifibrotic effects in vitro and in different models in vivo. JNK might thus be a novel molecular target for the treatment of fibrosis in SSc.

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Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor

Cited by 90 publications

References 19 publications

Functional p38 MAPK Identified by Biomarker Profiling of Pancreatic Cancer Restrains Growth through JNK Inhibition and Correlates with Improved Survival

Functional p38 MAPK Identified by Biomarker Profiling of Pancreatic Cancer Restrains Growth through JNK Inhibition and Correlates with Improved Survival

Regulated IRE1-dependent mRNA decay sets the threshold for dendritic cell survival

Jun N-terminal kinase as a potential molecular target for prevention and treatment of dermal fibrosis

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