Nonclinical Toxicology and Toxicokinetic Profile of an Oral Lanthionine Synthetase C-Like 2 (LANCL2) Agonist, BT-11

Leber, Andrew; Hontecillas, Raquel; Zoccoli-Rodriguez, Victoria; Ehrich, Marion; Davis, Jennifer L.; Chauhan, Jyoti; Bassaganya‐Riera, Josep

doi:10.1177/1091581819827509

Cited by 12 publications

(4 citation statements)

References 28 publications

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“…BT-11 (piperazine-1,4-diylbis((6-(1H-benzo[d]imidazol2-yl)pyridin-2-yl)methanone) dihydrochloride), an oral, gut-restricted, small molecule that activates lanthionine synthetase C-like 2 (LANCL2) ( Leber et al, 2019 ), has demonstrated to be able to lead to an increase in number and function of regulatory CD4 + T cells (Tregs) in Inflammatory bowel disease (IBD) and is programmed to be tested in EoE patients in a phase Ib study (NCT04835168) planned to start in January 2022. 5…”

Section: Focus On Type 2 Inflammation: the Protagonistsmentioning

confidence: 99%

Type 2 Inflammation in Eosinophilic Esophagitis: From Pathophysiology to Therapeutic Targets

et al. 2022

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Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease of the esophagus characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation, whose incidence is rising. It significantly affects patients’ quality of life and, if left untreated, results in fibrotic complications. Although broad consensus has been achieved on first-line therapy, a subset of patients remains non-responder to standard therapy. The pathogenesis of EoE is multifactorial and results from the complex, still mostly undefined, interaction between genetics and intrinsic factors, environment, and antigenic stimuli. A deep understanding of the pathophysiology of this disease is pivotal for the development of new therapies. This review provides a comprehensive description of the pathophysiology of EoE, starting from major pathogenic mechanisms (genetics, type 2 inflammation, epithelial barrier dysfunction, gastroesophageal reflux, allergens, infections and microbiota) and subsequently focusing on the single protagonists of type 2 inflammation (involved cells, cytokines, soluble effectors, surface proteins and transcription factors) that could represent present and future therapeutic targets, while summarizing previous therapeutic approaches in literature.

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Section: Focus On Type 2 Inflammation: the Protagonistsmentioning

confidence: 99%

Type 2 Inflammation in Eosinophilic Esophagitis: From Pathophysiology to Therapeutic Targets

et al. 2022

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“…As for α4β7 integrin, Siglecs are also found on the membranes of many immune cells, and they are involved, among other cell signaling pathways, in apoptosis [166]. Siglec-8 blockers (antolimab/lirentelimab mAb), which were originally applied for eosinophilic enteritis, provided a significant reduction in esophageal eosinophilic infiltrate with a high esophageal remission rate and a dysphagia score reduction in a subcohort of EoE patients [167]. A phase II/III, multicenter, double-blind, placebo-controlled RCT study (NCT04322708) specifically in EoE is currently ongoing.…”

Section: Drugs Targeting the Ige Pathwaymentioning

confidence: 99%

Mechanistic Insights into Eosinophilic Esophagitis: Therapies Targeting Pathophysiological Mechanisms

Massironi,

Mulinacci,

Gallo

et al. 2023

Cells

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Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized by eosinophilic infiltration of the esophagus. It arises from a complex interplay of genetic predisposition (susceptibility loci), environmental triggers (allergens and dietary antigens), and a dysregulated immune response, mainly mediated by type 2 T helper cell (Th2)-released cytokines, such as interleukin (IL)-4, IL-5, and IL-13. These cytokines control eosinophil recruitment and activation as well as tissue remodeling, contributing to the characteristic features of EoE. The pathogenesis of EoE includes epithelial barrier dysfunction, mast cell activation, eosinophil degranulation, and fibrosis. Epithelial barrier dysfunction allows allergen penetration and promotes immune cell infiltration, thereby perpetuating the inflammatory response. Mast cells release proinflammatory mediators and promote eosinophil recruitment and the release of cytotoxic proteins and cytokines, causing tissue damage and remodeling. Prolonged inflammation can lead to fibrosis, resulting in long-term complications such as strictures and dysmotility. Current treatment options for EoE are limited and mainly focus on dietary changes, proton-pump inhibitors, and topical corticosteroids. Novel therapies targeting key inflammatory pathways, such as monoclonal antibodies against IL-4, IL-5, and IL-13, are emerging in clinical trials. A deeper understanding of the complex pathogenetic mechanisms behind EoE will contribute to the development of more effective and personalized therapeutic strategies.

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“…Up until now, only a limited number of ABA analogues was biologically assessed and investigated as LANCL2 ligands, as well as other structurally different chemical entities [ 25 , 26 ]. Only one patented compound, namely, BT-11 (see Figure 1 ) [ 27 ], has been described as an LANCL2 agonist able to reduce inflammation in multiple mouse models of IBD (Omilancor, Phase 2 recently completed) [ 28 ], also with lead indications in ulcerative colitis (UC) and Crohn’s disease (CD) [ 29 ]. BT-11 was tested for general toxicity in studies in rats and dogs, revealing the compound to be a safe and well-tolerated oral drug candidate with no observed adverse effect at a level > 1000 mg/kg in in vivo studies [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

New Insights into the LANCL2-ABA Binding Mode towards the Evaluation of New LANCL Agonists

Scarano,

Di Palma,

Origlia

et al. 2023

Pharmaceutics

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The lanthionine synthetase C-like (LANCL) proteins include LANCL2, which is expressed in the central nervous system (CNS) and in peripheral tissues. LANCL2 exhibits glutathionylation activity and is involved in the neutralization of reactive electrophiles. Several studies explored LANCL2 activation as a validated pharmacological target for diabetes and inflammatory bowel disease. In this context, LANCL2 was found to bind the natural product abscisic acid (ABA), whose pre-clinical effectiveness in different inflammatory diseases was reported in the literature. More recently, LANCL2 attracted more attention as a valuable resource in the field of neurodegenerative disorders. ABA was found to regulate neuro-inflammation and synaptic plasticity to enhance learning and memory, exhibiting promising neuroprotective effects. Up until now, a limited number of LANCL2 ligands are known; among them, BT-11 is the only compound patented and investigated for its anti-inflammatory properties. To guide the design of novel putative LANCL2 agonists, a computational study including molecular docking and long molecular dynamic (MD) simulations of both ABA and BT-11 was carried out. The results pointed out the main LANCL2 ligand chemical features towards the following virtual screening of a novel putative LANCL2 agonist (AR-42). Biochemical assays on rat H9c2 cardiomyocytes showed a similar, LANCL2-mediated stimulation by BT-11 and by AR-42 of the mitochondrial proton gradient and of the transcriptional activation of the AMPK/PGC-1α/Sirt1 axis, the master regulator of mitochondrial function, effects that are previously observed with ABA. These results may allow the development of LANCL2 agonists for the treatment of mitochondrial dysfunction, a common feature of chronic and degenerative diseases.

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Nonclinical Toxicology and Toxicokinetic Profile of an Oral Lanthionine Synthetase C-Like 2 (LANCL2) Agonist, BT-11

Cited by 12 publications

References 28 publications

Type 2 Inflammation in Eosinophilic Esophagitis: From Pathophysiology to Therapeutic Targets

Type 2 Inflammation in Eosinophilic Esophagitis: From Pathophysiology to Therapeutic Targets

Mechanistic Insights into Eosinophilic Esophagitis: Therapies Targeting Pathophysiological Mechanisms

New Insights into the LANCL2-ABA Binding Mode towards the Evaluation of New LANCL Agonists

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