Integrin modulators: a patent review

Kapp, Tobias G.; Rechenmacher, Florian; Sobahi, Tariq R.; Kessler, Horst

doi:10.1517/13543776.2013.818133

Cited by 66 publications

(64 citation statements)

References 127 publications

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“…Although this effect of av inhibition may destabilize the protective fibrous cap, 49 it remains unknown whether integrin inhibitors will show similar effects on endothelial and smooth muscle phenotype in advanced atherosclerotic plaques. With multiple avb3 antagonists currently undergoing clinical trials for the treatment of psoriasis, arthritis, and cancer, 50 the use of these agents in patients at risk of cardiovascular events should be carefully weighed. ajp.amjpathol.org -The American Journal of Pathology…”

Section: Flow-induced Inflammation Requires Avb3mentioning

confidence: 99%

αvβ3 Integrins Mediate Flow-Induced NF-κB Activation, Proinflammatory Gene Expression, and Early Atherogenic Inflammation

Chen

Green

Yurdagul

et al. 2015

The American Journal of Pathology

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Endothelial cell interactions with transitional matrix proteins, such as fibronectin, occur early during atherogenesis and regulate shear stress-induced endothelial cell activation. Multiple endothelial cell integrins bind transitional matrix proteins, including a5b1, avb3, and avb5. However, the role these integrins play in mediating shear stress-induced endothelial cell activation remains unclear. Therefore, we sought to elucidate which integrin heterodimers mediate shear stress-induced endothelial cell activation and early atherogenesis. We now show that inhibiting avb3 integrins (S247, siRNA), but not a5b1 or avb5, blunts shear stress-induced proinflammatory signaling (NF-kB, p21-activated kinase) and gene expression (ICAM1, VCAM1). Importantly, inhibiting avb3 did not affect cytokine-induced proinflammatory responses or inhibit all shear stress-induced signaling, because Akt, endothelial nitric oxide synthase, and extracellular regulated kinase activation remained intact. Furthermore, inhibiting av integrins (S247), but not a5 (ATN-161), in atherosclerosis-prone apolipoprotein E knockout mice significantly reduced vascular remodeling after acute induction of disturbed flow. S247 treatment similarly reduced early diet-induced atherosclerotic plaque formation associated with both diminished inflammation (expression of vascular cell adhesion molecule 1, plaque macrophage content) and reduced smooth muscle incorporation. Inducible, endothelial cell-specific av integrin deletion similarly blunted inflammation in models of disturbed flow and diet-induced atherogenesis but did not affect smooth muscle incorporation. Our studies identify avb3 as the primary integrin heterodimer mediating shear stress-induced proinflammatory responses and as a key contributor to early atherogenic inflammation. (Am J Pathol 2015 http://dx.doi.org/10.1016/j.ajpath.2015 Although traditional risk factors for atherosclerosis, such as hypercholesterolemia and hyperglycemia, are systemic throughout the circulation, atherosclerotic plaques form at discrete areas of the vasculature where vessel geometry results in altered hemodynamics.1,2 Endothelial cells respond to the frictional force generated by these flow patterns, termed shear stress, and convert them into intracellular biochemical signals that critically modulate endothelial cell function. In straight regions of arteries, shear stress generated by unidirectional, laminar flow promotes nitric oxide production and limits endothelial cell activation, consistent with the absence of atherosclerosis in these areas.1,2 In contrast, shear stress generated by disturbed flow patterns, such as those observed at sites of vessel branch points, bifurcations, and curvatures, results in endothelial cell activation with enhanced proinflammatory gene expression [intercellular adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1)] and permeability.

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Section: Flow-induced Inflammation Requires Avb3mentioning

confidence: 99%

αvβ3 Integrins Mediate Flow-Induced NF-κB Activation, Proinflammatory Gene Expression, and Early Atherogenic Inflammation

Chen

Green

Yurdagul

et al. 2015

The American Journal of Pathology

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“…Although the roles of a number of cytoskeletal genes and proteins mediated by HBx have not been determined, the reviewed studies provide insights into the function of these factors in the development of HBV-associated HCC. Chemotherapeutic agents that are able to induce stabilization of cytoskeleton-associated proteins to restrict movement, as well as limit intracellular processes, have been studied as potential therapeutic agents for certain tumors (46,73). Therefore, it is possible that clarifying the underlying regulatory mechanisms of cytoskeleton-associated proteins during HBV infection may facilitate the identification of novel potential therapeutic targets for HBV-associated HCC.…”

Section: Resultsmentioning

confidence: 99%

“…Integrins are heterodimeric transmembrane adhesion receptors composed of 18 α-subunits and 8 β-subunits, and may recognize specific peptide motifs located in ECM components, including fibronectin, vitronectin, laminin, hyaluronan and collagen (46,47). HBV replication reduces the formation of focal adhesions and the actin concentration at the cell periphery, resulting in a significant reduction of adhesion to laminin in cells infected with HBV (48).…”

Section: The Cellular Cytoskeletal Proteins Associated With Cell Adhementioning

confidence: 99%

The regulation of proteins associated with the cytoskeleton by hepatitis B virus X protein during hepatocarcinogenesis

et al. 2017

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Abstract. Hepatocellular carcinoma (HCC) is a major malignant disease worldwide, and chronic hepatitis B virus (HBV) infection is one of the primary causes for this type of cancer. Hepatitis B virus X protein (HBx) is a non-structural protein encoded by the viral genome that has significant effects on the pathogenesis of HCC. With the development of high-throughput assays and technologies, the abnormal HBx-induced expression of certain cellular proteins with assorted biological functions has been investigated. These target proteins identified by various methods include specific proteins associated with the cellular cytoskeleton, which contribute to HBx-induced hepatocarcinogenesis. In addition, the cytoskeletal proteins deregulated by HBx are involved in cell morphogenesis, adhesion, migration and proliferation. This review aims to summarize the current understanding of the expression profiles of HBx-associated cytoskeletal proteins, as well as their complex functions and underlying mechanisms in hepatocarcinogenesis. Considering that the potential therapeutics for various types of tumors may function through the stabilization of cytoskeletal proteins in order to restrict cellular movement and limit intracellular processes, clarifying the mechanisms underlying protein-associated cytoskeleton dysregulation by HBx may provide novel possibilities and potent therapeutic targets for HBV-associated HCC. Contents

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“…MK0429: MK0429 is a small, active, potent, non-peptide αvβ3 integrin inhibitor [23,56]. It functions to have potent inhibition activity for osteoclast formation and osteoclastic bone resorption.…”

Section: Integrin Antagonists In Tumor and Angiogenesis Inhibitionmentioning

confidence: 99%

Pharmacological and Clinical Importance of Integrin Antagonists in Treatment of Cancer

Santhosh¹

2014

J Cell Sci Ther

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Integrins are heterodimeric molecules that are composed of 18 α-subunits and 8 β-subunits. They exist in 24 distinctive shapes based on combination of these sub-units and are mainly responsible for the adhesion of extracellular matrix (ECM) and immunoglobulin family molecules. Integrins mediate adhesion of epithelial cells to the basement membrane and also help in the migration, proliferation and survival of tumor cells. Studies also reveal that certain integrins act as markers for tumor cells and they also assist in both tumor progression and apoptosis. Studies reveal that unligated integrins in association with caspase 8 result in inhibition of ECM adhesion might result and integrin mediated death (IMD) on the other hand integrins in association with oncogenes or receptor tyrosine kinases can result in enhanced tumorigenesis. Among several types of integrins, αvβ3 and α 5 β 1 have gained importance in anti-angiogenesis studies.Hence the role of antiangiogenesis antagonists has come into light. These include a variety of monoclonal antibodies and peptides. Each one of them has their own mechanism of action and antiangiogenesis activity. Current review aims at studying the phase 1 and 2 trails of these antagonists for anti-angiogenic function.

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Integrin modulators: a patent review

Cited by 66 publications

References 127 publications

αvβ3 Integrins Mediate Flow-Induced NF-κB Activation, Proinflammatory Gene Expression, and Early Atherogenic Inflammation

αvβ3 Integrins Mediate Flow-Induced NF-κB Activation, Proinflammatory Gene Expression, and Early Atherogenic Inflammation

The regulation of proteins associated with the cytoskeleton by hepatitis B virus X protein during hepatocarcinogenesis

Pharmacological and Clinical Importance of Integrin Antagonists in Treatment of Cancer

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