Emerging therapeutic opportunities for integrin inhibitors

Slack, Robert J.; Macdonald, Simon J. F.; Roper, James A.; Jenkins, Gisli; Hatley, Richard J. D.

doi:10.1038/s41573-021-00284-4

Cited by 305 publications

(249 citation statements)

References 197 publications

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“…AQP9 has been implicated in both activation and inhibition of cellular motility, depending upon the anabolic signaling pathways in operation. Reduced AQP9 expression can compromise protrusion formation; AQP9 transfection in HEK-293 cells enabled formation of bleb-like membrane protrusions, which were blocked by the AQP9 antagonist HTS13286 [ 128 , 129 ]. Conversely, overexpression of AQP9 reduced migration and invasion in hepatocyte carcinoma cells, an effect that was reversed by Wnt/β-catenin activation [ 125 ].…”

Section: Aquaporins As Drug Targets In Glioblastoma Multiforme Tumorsmentioning

confidence: 99%

Novel Ion Channel Targets and Drug Delivery Tools for Controlling Glioblastoma Cell Invasiveness

Varricchio

Ramesh

Yool

2021

IJMS

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Comprising more than half of all brain tumors, glioblastoma multiforme (GBM) is a leading cause of brain cancer-related deaths worldwide. A major clinical challenge is presented by the capacity of glioma cells to rapidly infiltrate healthy brain parenchyma, allowing the cancer to escape control by localized surgical resections and radiotherapies, and promoting recurrence in other brain regions. We propose that therapies which target cellular motility pathways could be used to slow tumor dispersal, providing a longer time window for administration of frontline treatments needed to directly eradicate the primary tumors. An array of signal transduction pathways are known to be involved in controlling cellular motility. Aquaporins (AQPs) and voltage-gated ion channels are prime candidates as pharmacological targets to restrain cell migration in glioblastoma. Published work has demonstrated AQPs 1, 4 and 9, as well as voltage-gated potassium, sodium and calcium channels, chloride channels, and acid-sensing ion channels are expressed in GBM and can influence processes of cell volume change, extracellular matrix degradation, cytoskeletal reorganization, lamellipodial and filopodial extension, and turnover of cell-cell adhesions and focal assembly sites. The current gap in knowledge is the identification of optimal combinations of targets, inhibitory agents, and drug delivery systems that will allow effective intervention with minimal side effects in the complex environment of the brain, without disrupting finely tuned activities of neuro-glial networks. Based on published literature, we propose that co-treatments using AQP inhibitors in addition to other therapies could increase effectiveness, overcoming some limitations inherent in current strategies that are focused on single mechanisms. An emerging interest in nanobodies as drug delivery systems could be instrumental for achieving the selective delivery of combinations of agents aimed at multiple key targets, which could enhance success in vivo.

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Section: Aquaporins As Drug Targets In Glioblastoma Multiforme Tumorsmentioning

confidence: 99%

Novel Ion Channel Targets and Drug Delivery Tools for Controlling Glioblastoma Cell Invasiveness

Varricchio

Ramesh

Yool

2021

IJMS

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“…Currently, there are three therapeutics venture companies in US that exclusively targeting the integrin family and reached clinical trials [6]. Two of these companies have been invested over $200 M from pharmaceutical companies including Novartis, AbbVie, in total and both listed on NASDAQ after 5 years of foundation.…”

Section: Trends Of Target-integrins For Fibrosismentioning

confidence: 99%

“…The above history of RGD peptide starting from the use in the elution buffer, and the established pharmacophore may explain why general interests in integrininhibitors converge on αv-integrins. Inhibitors of integrins αvβ1 and αvβ6 is the leading pack in 2021 [6].…”

Section: Trends Of Target-integrins For Fibrosismentioning

confidence: 99%

“…Currently, most drugs in clinical trials are the former and the latter are limited especially after simtuzumab (anti-LOXL2) [4] and seronsertive (ASK-1 inhibitor) [5] fell in phase II and III, respectively. In this situation, integrin inhibitors have an emerging therapeutic opportunity in fibrosis [6]. Integrins are a receptor for matrix proteins that essentially consists of fibrosis tissues, and some integrins show activation potential for latent-TGFβ [7].…”

Section: Introductionmentioning

confidence: 99%

“…What the history of αv-integrin inhibitors tells us αv-integrins activate TGFβ and protect against fibrosis when deleted. Nevertheless, no approved αv-inhibitor for fibrosis and other diseases is in the clinic, despite drugs against integrins, αIIbβ3 [44], α4β1 [45], α4β7 [46], and αLβ2 [47] [48] are making big market [6]. It has been difficult to give specificity to a small molecule inhibitor to individual αv-integrins, with the same pharmacophore shared.…”

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confidence: 99%

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New Therapeutic Targets for Hepatic Fibrosis in the Integrin Family, α8β1 and α11β1, Induced Specifically on Activated Stellate Cells

Yokosaki¹,

Nishimichi²

2021

Preprint

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Huge effort has been devoted to developing drugs targeting integrins over 30 years, because of the primary roles of integrins in the cell-matrix milieu. Five αv-containing integrins, in the 24 family members, have been a central target of fibrosis. Currently, a small molecule against αvβ1 is undergoing a clinical trial for NASH-associated fibrosis as a rare reagent aiming at fibrogenesis. Latent TGFβ activation, a distinct talent of αv-integrins, has been intriguing as therapeutic target. None of the αv-integrin inhibitors, however, has been in the clinical market. αv-integrins commonly recognize an Arg-Gly-Asp (RGD) sequence, and thus the pharmacophore of inhibitors for the 5-integrins is based on the same RGD structure. The RGD preference of the integrins, at the same time, dilutes ligand specificity, as the 5-integrins share ligands containing RGD sequence such as fibronectin. With the inherent little specificity in both drugs and targets, “disease specificity” has become less important for the inhibitors than blocking as many αv-integrins. In fact, an almighty inhibitor for αv-integrins, pan-αv, was in a clinical trial. On the contrary, approved integrin inhibitors are all specific to target integrins, which are expressed in cell-type specific manner: αIIbβ3 on platelets, α4β1, α4β7 and αLβ2 on leukocytes. Herein, “disease specific” integrins would serve as attractive targets. α8β1 and α11β1 are selectively expressed in hepatic stellate cells (HSCs) and distinctively induced upon culture activation. The exceptional specificity to activated HSCs reflects rather “pathology specific” nature of these new integrins. The monoclonal antibodies against α8β1 and α11β1 in preclinical examinations may illuminate the road to the first medical reagents.

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Shear‐Responsive Drug Delivery Systems in Medical Devices: Focus on Thrombosis and Bleeding

Shirejini

Carberry

Alt

et al. 2023

Adv Funct Materials

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Cardiovascular disease is the leading cause of death worldwide. Blood‐contacting medical devices provide critical support for patients with severe respiratory and/or cardiac failure. High shear stress zones and non‐biocompatible circuit can increase the risk of thrombus formation in patients. These thrombi restrict blood flow through the circuits and travel to the lungs and brain, creating significant consequences. Antithrombotic drugs are used to lower this risk, but they also raise the incidence of bleeding problems. This article explores the delicate balance between thrombosis and bleeding in medical devices by examining platelet activation and thrombosis formation under shear stress. The feasibility of a shear‐responsive nanomedicine‐based drug delivery system has been explored as a potential approach for targeted administration of antithrombotic medications to lower systemic drug levels and reduce the bleeding risk. Furthermore, the lack of in vitro platforms to investigate the biological behavior of antithrombotic nanoparticles is impeding their clinical translation. As a result, microfluidic technology offers a platform for investigating nanoparticle behavior in vitro and linking it to their performance in vivo. Finally, the challenges and factors that affect the functionality, stability, and circulation time of liposomal drugs are investigated to improve their efficacy for targeted drug administration in medical devices.

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Emerging therapeutic opportunities for integrin inhibitors

Cited by 305 publications

References 197 publications

Novel Ion Channel Targets and Drug Delivery Tools for Controlling Glioblastoma Cell Invasiveness

Novel Ion Channel Targets and Drug Delivery Tools for Controlling Glioblastoma Cell Invasiveness

New Therapeutic Targets for Hepatic Fibrosis in the Integrin Family, α8β1 and α11β1, Induced Specifically on Activated Stellate Cells

Shear‐Responsive Drug Delivery Systems in Medical Devices: Focus on Thrombosis and Bleeding

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