Thermostable small-molecule inhibitor of angiogenesis and vascular permeability that suppresses a pERK-FosB/ΔFosB–VCAM-1 axis

Li, Yue; Alhendi, Ahmad M. N.; Yeh, Mei-Chun; Elahy, Mina; Santiago, Fernando S.; Deshpande, Nandan P.; Wu, Ben J.; Chan, Enoch; Inam, Shafqat; Prado-Lourenço, Leonel; Marchand, Jessica; Joyce, Rohan D.; Wilkinson-White, Lorna; Raftery, Mark J.; Zhu, Meidong; Adamson, Samuel; Barnat, François; Viaud-Quentric, Karen; Sockler, Jim; Mackay, Joel P.; Chang, Andrew; Marcuccio, Sebastian M.; Khachigian, Levon M.

doi:10.1126/sciadv.aaz7815

Cited by 20 publications

(21 citation statements)

References 56 publications

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“… 22 , 23 Flow cytometry revealed BT2 inhibition of IL-1ß inducible ICAM-1 expression in HMEC-1 cells ( Figure 1A ). In contrast, BT3 17 (2-amino-10-ethyldibenzo[b,f][1,4] oxazepin-11 (10H)-one), a close structural analogue of BT2 ( Figure 1B ) was unable to do so ( Figure 1A ). BT2 inhibited ICAM-1 expression in a dose-dependent manner ( Figure 1C ).…”

Section: Resultsmentioning

confidence: 99%

“…We recently demonstrated the capacity of the dibenzoxazepinone BT2 (10-ethyl-11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepin-2-yl)-carbamic acid ethyl ester) to inhibit angiogenesis and vascular permeability. 17 This led us to explore the anti-inflammatory properties of BT2. IL-1ß and the pro-inflammatory cell adhesion molecule ICAM-1 have each strongly been implicated in the pathogenesis of RA.…”

Section: Resultsmentioning

confidence: 99%

“…BT2 (10-ethyl-11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepin-2-yl)-carbamic acid ethyl ester) was prepared by reacting commercially available 2-amino-10-ethyldibenzo[b,f][1,4] oxazepin-11 (10H)-one (BT3) with diethyl pyrocarbonate as described 17 by Advanced Molecular Technologies, Scoresby (Vic).…”

Section: Methodsmentioning

confidence: 99%

“…BT2 inhibited ICAM-1 expression in a dose-dependent manner ( Figure 1C). BT2 inhibition of vascular cell adhesion molecule (VCAM)-1 17 served as a further control ( Figure 1D).…”

Section: Bt2 Inhibits Intercellular Adhesion Molecule (Icam)-1 Expresmentioning

confidence: 99%

“…We recently identified a dibenzoxazepinone BT2 from a high-throughput chemical screen 17 that inhibits ERK phosphorylation (pERK), and suppresses the inducible expression of the basic region-leucine zipper proteins FosB/∆FosB and c-Fos, both members of the activator protein-1 (AP-1) family of dimeric transcription factors. 18 AP-1 regulates gene expression in response to a range of pathologic stimuli including cytokines, growth factors, various stresses and viral and bacterial infection 18 and has been implicated in the pathogenesis of cancer, cardiovascular disease and a range of inflammatory diseases.…”

Section: Introductionmentioning

confidence: 99%

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BT2 Suppresses Human Monocytic-Endothelial Cell Adhesion, Bone Erosion and Inflammation

Yeh

et al. 2021

JIR

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Introduction: Inflammation and bone erosion are processes key to the pathogenesis of rheumatoid arthritis, a systemic autoimmune disease causing progressive disability and pain, impacting around 1.3 million people in the United States alone. However, many patients do not respond sufficiently to existing therapies or benefit is not sustained and alternate therapeutic approaches are lacking. We recently identified the dibenzoxazepinone BT2, which inhibits ERK phosphorylation, from a high-throughput chemical screen and identified its ability to inhibit angiogenesis and vascular leakiness. Methods: Here we evaluated BT2 for potential anti-inflammatory activity in in vitro models of human monocytic-endothelial cell adhesion, monocytic cell extravasation and collagen antibody-induced arthritis in mice. Results: BT2 inhibits human monocytic cell adhesion to IL-1ß-treated human endothelial cells and inhibits monocytic transendothelial migration toward MCP-1. In mice rendered arthritic, single systemic administration of BT2 prevented footpad swelling, bone destruction and TRAP + cells in the joints. BT2 suppressed inducible circulating levels of IL-1ß, IL-2 and IL-6 to normal levels without affecting levels of IL-4 or IL-10 among other cytokines. BT2 also inhibited the expression of pro-inflammatory adhesion molecules ICAM-1 and VCAM-1 in arthritic joints. There was no evidence of toxicity following intraperitoneal, gavage or intraarticular administration of BT2. Conclusion: BT2 is a novel small molecule inhibitor of joint inflammation, bone erosion, pro-inflammatory cytokine and adhesion molecule expression. This suggests the potential clinical utility of BT2 as a new anti-inflammatory agent.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…BT2 inhibited ICAM-1 expression in a dose-dependent manner ( Figure 1C). BT2 inhibition of vascular cell adhesion molecule (VCAM)-1 17 served as a further control ( Figure 1D).…”

Section: Bt2 Inhibits Intercellular Adhesion Molecule (Icam)-1 Expresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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BT2 Suppresses Human Monocytic-Endothelial Cell Adhesion, Bone Erosion and Inflammation

Yeh

et al. 2021

JIR

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Posttranslational modifications in retinal degeneration diseases: An update on the molecular basis and treatment

Yao,

Mou,

Jiang

et al. 2024

Brain-X

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Noninherited diseases and age‐associated vision loss are often associated with retinal degeneration. The retina is a postmitotic neural tissue lacking endogenous regeneration capacity. Therefore, understanding the mechanism of retinal degeneration in diseases is pivotal. Posttranslational modifications (PTMs) determine protein function during physiological and pathological processes, including signal transduction, protein localization, and protein activation. Advanced detection technologies have revealed over 400 different PTMs including acetylation, methylation, phosphorylation, ubiquitination and SUMOylation. Here, we discuss PTMs in retinal degeneration diseases to aid in our understanding of their molecular basis and suggest potential future clinical treatment.

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Current developments of gene therapy in human diseases

Liu,

Li,

Zhu

et al. 2024

MedComm

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Gene therapy has witnessed substantial advancements in recent years, becoming a constructive tactic for treating various human diseases. This review presents a comprehensive overview of these developments, with a focus on their diverse applications in different disease contexts. It explores the evolution of gene delivery systems, encompassing viral (like adeno‐associated virus; AAV) and nonviral approaches, and evaluates their inherent strengths and limitations. Moreover, the review delves into the progress made in targeting specific tissues and cell types, spanning the eye, liver, muscles, and central nervous system, among others, using these gene technologies. This targeted approach is crucial in addressing a broad spectrum of genetic disorders, such as inherited lysosomal storage diseases, neurodegenerative disorders, and cardiovascular diseases. Recent clinical trials and successful outcomes in gene therapy, particularly those involving AAV and the clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR‐associated proteins, are highlighted, illuminating the transformative potentials of this approach in disease treatment. The review summarizes the current status of gene therapy, its prospects, and its capacity to significantly ameliorate patient outcomes and quality of life. By offering comprehensive analysis, this review provides invaluable insights for researchers, clinicians, and stakeholders, enriching the ongoing discourse on the trajectory of disease treatment.

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Thermostable small-molecule inhibitor of angiogenesis and vascular permeability that suppresses a pERK-FosB/ΔFosB–VCAM-1 axis

Cited by 20 publications

References 56 publications

BT2 Suppresses Human Monocytic-Endothelial Cell Adhesion, Bone Erosion and Inflammation

BT2 Suppresses Human Monocytic-Endothelial Cell Adhesion, Bone Erosion and Inflammation

Posttranslational modifications in retinal degeneration diseases: An update on the molecular basis and treatment

Current developments of gene therapy in human diseases

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