Sa1757 Targeting Innate Immune Receptors to Treat Inflammatory Bowel Disease: Preclinical Activity of IMO-9200, an Antagonist of TLRS 7, 8, and 9 in Mouse Models of Colitis

Zhu, Fu‐Gang; Wang, Daqing; Jiang, Wayne; Bhagat, Lakshmi; Agrawal, Sudhir

doi:10.1016/s0016-5085(15)31073-8

Cited by 6 publications

(4 citation statements)

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“…From a phase I clinical trial, it showed a safe and well-tolerated profile in healthy subjects. IMO-9200 was evaluated as potent treatment against inflammatory bowel disease [350].…”

Section: Oligonucleotidesmentioning

confidence: 99%

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

Patinote

Karroum

Moarbess

et al. 2020

European Journal of Medicinal Chemistry

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a b s t r a c tThe discovery of the TLRs family and more precisely its functions opened a variety of gates to modulate immunological host responses. TLRs 7/8 are located in the endosomal compartment and activate a specific signaling pathway in a MyD88-dependant manner. According to their involvement into various autoimmune, inflammatory and malignant diseases, researchers have designed diverse TLRs 7/8 ligands able to boost or block the inherent signal transduction. These modulators are often small synthetic compounds and most act as agonists and to a much lesser extent as antagonists. Some of them have reached preclinical and clinical trials, and only one has been approved by the FDA and EMA, imiquimod. The key to the success of these modulators probably lies in their combination with other therapies as recently demonstrated. We gather in this review more than 360 scientific publications, reviews and patents, relating the extensive work carried out by researchers on the design of TLRs 7/8 modulators, which are classified firstly by their biological activities (agonist or antagonist) and then by their chemical structures, which total syntheses are not discussed here. This review also reports about 90 clinical cases, thereby showing the biological interest of these modulators in multiple pathologies.

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“…From a phase I clinical trial, it showed a safe and well-tolerated profile in healthy subjects. IMO-9200 was evaluated as potent treatment against inflammatory bowel disease [350].…”

Section: Oligonucleotidesmentioning

confidence: 99%

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

Patinote

Karroum

Moarbess

et al. 2020

European Journal of Medicinal Chemistry

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“…Recently, IMO-3100 was evaluated in a 4-week phase 2 trial in psoriasis patients (NCT01622348). IMO-9200, a trinary antagonist of TLRs 7/8/9, ameliorates SLE progression in mouse model and shows safety and tolerance in healthy subjects [ 56 ]. IMO-8400 is also a dual antagonist of TLRs 7/9 that completed a phase 2 trial in psoriasis pathogenesis (NCT01899729) and dermatomyositis (NCT02612857).…”

Section: Tlr7 Implication In a Variety Of Clinical Diseasesmentioning

confidence: 99%

Recent Advances on Small-Molecule Antagonists Targeting TLR7

Zheng

Bonnet

2023

Molecules

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Toll-like receptor 7 (TLR7) is a class of pattern recognition receptors (PRRs) recognizing the pathogen-associated elements and damage and as such is a major player in the innate immune system. TLR7 triggers the release of pro-inflammatory cytokines or type-I interferons (IFN), which is essential for immunoregulation. Increasing reports also highlight that the abnormal activation of endosomal TLR7 is implicated in various immune-related diseases, carcinogenesis as well as the proliferation of human immunodeficiency virus (HIV). Hence, the design and development of potent and selective TLR7 antagonists based on small molecules or oligonucleotides may offer new tools for the prevention and management of such diseases. In this review, we offer an updated overview of the main structural features and therapeutic potential of small-molecule antagonists of TLR7. Various heterocyclic scaffolds targeting TLR7 binding sites are presented: pyrazoloquinoxaline, quinazoline, purine, imidazopyridine, pyridone, benzanilide, pyrazolopyrimidine/pyridine, benzoxazole, indazole, indole, and quinoline. Additionally, their structure-activity relationships (SAR) studies associated with biological activities and protein binding modes are introduced.

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“…We also investigated the use of PS-ODNs and PS-ORNs containing modifications that neutralize the immune response as antagonists of TLR-7/9 and TLR-7/8/9 [ 92 , 93 , 94 ]. We showed that in animal models of autoimmune and inflammatory diseases, including psoriasis [ 95 ], lupus [ 96 ], Duchenne muscular dystrophy [ 96 ], colitis [ 97 ], and genetically defined lymphomas [ 98 ], such antagonists do indeed provide therapeutic benefit. Clinical benefit has also been shown in patients with psoriasis [ 99 ] and Waldenström’s macroglobulinemia [ 100 ].…”

Section: Paying the Tolls: The Role Of Sequence And Modificationsmentioning

confidence: 99%