Identification of a Novel Inhibitor of the NF-κB Pathway

Misra-Press, Anita; McMillan, Michael; Cudaback, Eiron; Qabar, Maher; Ruan, Fengying; Nguyen, Minh Tam; Vaisar, Tomáš; Nakanishi, Hiroyuki; Kahn, Michaël

doi:10.2174/1568014024606566

Cited by 8 publications

(15 citation statements)

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“…We have previously reported (29) that MOL 294 is a potent (2.5 M IC 50 ) inhibitor of NF-B-mediated VCAM-1 expression in HUVECs and bound and inhibited the reductase activity of Trx in vitro. We now show that treatment of A549 lung epithelial cells with MOL 294 leads to a dose-dependent reduction of cellular Trx activity with an IC 50 Ͻ5 M. Furthermore, we demonstrate that the treatment of A549 cells with MOL 294 leads to a dose-dependent inhibition of the LPS-induced (presumably Trx-mediated) reduction of the S-NO group of a cysteine residue of p65.…”

Section: Discussionmentioning

confidence: 99%

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A Small Molecule Inhibitor of Redox-Regulated NF-κB and Activator Protein-1 Transcription Blocks Allergic Airway Inflammation in a Mouse Asthma Model

Henderson

Emil

Teo

et al. 2002

The Journal of Immunology

103

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An oxidant/antioxidant imbalance is seen in the lungs of patients with asthma. This oxidative stress in asthmatic airways may lead to activation of redox-sensitive transcription factors, NF-κB and AP-1. We examined the effect of the small molecule inhibitor of redox-regulated NF-κB and AP-1 transcription, MOL 294 on airway inflammation and airway hyperreactivity (AHR) in a mouse model of asthma. MOL 294 is a potent nonpeptide inhibitor of NF-κB and AP-1 based upon a β-strand template that binds to and inhibits the cellular redox protein thioredoxin. BALB/c mice after i.p. OVA sensitization (day 0) were challenged with intranasal OVA on days 14, 25, 26, and 27. MOL 294, administered intranasal on days 25–27, blocked the airway inflammatory response to OVA assessed 24 h after the last OVA challenge on day 28. MOL 294 reduced eosinophil, IL-13, and eotaxin levels in bronchoalveolar lavage fluid and airway tissue eosinophilia and mucus hypersecretion. MOL 294 also decreased AHR in vivo to methacholine. These results support redox-regulated transcription as a therapeutic target in asthma and demonstrate that selective inhibitors can reduce allergic airway inflammation and AHR.

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Section: Discussionmentioning

confidence: 99%

“…We have recently developed a novel small molecule inhibitor of NF-B and AP-1 transcription, MOL 294 (29). The molecular target of MOL-294 appears to be the oxidoreductase, thioredoxin (Trx).…”

mentioning

confidence: 99%

A Small Molecule Inhibitor of Redox-Regulated NF-κB and Activator Protein-1 Transcription Blocks Allergic Airway Inflammation in a Mouse Asthma Model

Henderson

Emil

Teo

et al. 2002

The Journal of Immunology

103

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“…We constructed a limited array (2 ϫ 6) where X was either NHCH 3 or NHBn and Y was methyl, phenyl, m-cyanophenyl, m-nitrophenyl, macetylaniline, or m-methylbenzoate. These analogs were evaluated for their ability to inhibit transcription in transiently transfected human lung epithelial A549 cells from either an AP-1 or NF-B reporter (22). One compound, PNRI-299 (Fig.…”

Section: Development Of Small-molecule Inhibitor Of Ap-1 Transcriptiomentioning

confidence: 99%

“…Through the utilization of 20-aa side chains displayed on a limited array of topological motifs (i.e., the common secondary structures, reverse turns, extended strands, and ␣-helices), nature has provided the elements required to delineate a multitude of ligand-receptor, enzyme-substrate interactions, and other signal transduction processes. We have used an extended-strand templated library to develop a small-molecule inhibitor of TRX and NF-B transcription (22,23). Here, we use a chemogenomic approach to develop a small-molecule inhibitor of redox-regulated AP-1 transcription and validate it as a therapeutic target for asthma.…”

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confidence: 99%

Chemogenomic identification of Ref-1/AP-1 as a therapeutic target for asthma

Nguyen

Teo

Matsuda

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Asthma is characterized by an oxidant͞antioxidant imbalance in the lungs leading to activation of redox-sensitive transcription factors, nuclear factor B (NF-B), and activator protein-1 (AP-1). To develop therapeutic strategies for asthma, we used a chemogenomics approach to screen for small molecule inhibitor(s) of AP-1 transcription. We developed a ␤-strand mimetic template that acts as a reversible inhibitor (pseudosubstrate) of redox proteins. This template incorporates an enedione moiety to trap reactive cysteine nucleophiles in the active sites of redox proteins. Specificity for individual redox factors was achieved through variations in X and Y functionality by using a combinatorial library approach. A limited array (2 ؋ 6) was constructed where X was either NHCH 3

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“…Incorporation of such inhibitors in endothelial cell-specific drug targeting systems can theoretically overcome these undesired side effects (8). The antioxidant and metal-chelating compound pyrrolidine dithiocarbamate (PDTC) (21), the glucocorticoid dexamethasone (Dex) (43), the thioredoxin inhibitor methyl-(4R/S)-4-hydroxy-4-[((5S,8S)/(5R,8R))-8-methyl-1,3-dioxo-2phenyl-2,3,5,8-tetrahydro-1H- [1,2,4]triazolo[1,2-a]pyridazin-5-yl]-2-butynoate (MOL-294) (19), and the p38 MAPK inhibitor 4-(4-(4-fluorophenyl)-1-(3-phenylpropyl)-5-(4-pyridinyl)-1H-imidazol-2-yl)-3-butyn-1-ol (RWJ-67657) (27) are potential candidates for incorporation in drug targeting constructs. However, limited data are available on quantitative comparison of the effects of these anti-inflammatory drugs on endothelial cell gene expression under proinflammatory conditions.…”

mentioning

confidence: 99%

Differential effects of NF-κB and p38 MAPK inhibitors and combinations thereof on TNF-α- and IL-1β-induced proinflammatory status of endothelial cells in vitro

Kułdo¹,

Westra²,

Ásgeirsdóttir³

et al. 2005

American Journal of Physiology-Cell Physiology

135

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Endothelial cells actively participate in inflammatory events by regulating leukocyte recruitment via the expression of inflammatory genes such as E-selectin, VCAM-1, ICAM-1, IL-6, IL-8, and cyclooxygenase (COX)-2. In this study we showed by real-time RT-PCR that activation of human umbilical vein endothelial cells (HUVEC) by TNF-alpha and IL-1beta differentially affected the expression of these inflammatory genes. Combined treatment with TNF-alpha and IL-1beta resulted in nonadditive, additive, and even synergistic induction of expression of VCAM-1, IL-8, and IL-6, respectively. Overexpression of dominant-negative inhibitor kappaB protein blocking NF-kappaB signaling confirmed a major role of this pathway in controlling both TNF-alpha- and IL-1beta-induced expression of most of the genes studied. Although dexamethasone exerted limited effects at 1 muM, the thioredoxin inhibitor MOL-294, which regulates the redox state of NF-kappaB, mainly inhibited adhesion molecule expression. Its most pronounced effect was seen on VCAM-1 mRNA levels, especially in IL-1beta-activated endothelium. One micromolar RWJ-67657, an inhibitor of p38 MAPK activity, diminished TNF-alpha- and IL-1beta-induced expression of IL-6, IL-8, and E-selectin but had little effect on VCAM-1 and ICAM-1. Combined treatment of HUVEC with MOL-294 and RWJ-67657 resulted in significant blocking of the expression of E-selectin, IL-6, IL-8, and COX-2. The inhibitory effects were much stronger than those observed with single drug treatment. Application of combinations of drugs that affect multiple targets in activated endothelial cells may therefore be considered as a potential new therapeutic strategy to inhibit inflammatory disease activity.

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Identification of a Novel Inhibitor of the NF-κB Pathway

Cited by 8 publications

References 0 publications

A Small Molecule Inhibitor of Redox-Regulated NF-κB and Activator Protein-1 Transcription Blocks Allergic Airway Inflammation in a Mouse Asthma Model

A Small Molecule Inhibitor of Redox-Regulated NF-κB and Activator Protein-1 Transcription Blocks Allergic Airway Inflammation in a Mouse Asthma Model

Chemogenomic identification of Ref-1/AP-1 as a therapeutic target for asthma

Differential effects of NF-κB and p38 MAPK inhibitors and combinations thereof on TNF-α- and IL-1β-induced proinflammatory status of endothelial cells in vitro

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