RESUMEN
Tyrosine kinase 2 (TYK2) mediates cytokine signaling through type 1 interferon, interleukin (IL)-12/IL-23, and the IL-10 family. There appears to be an association between TYK2 genetic variants and inflammatory conditions, and clinical evidence suggests that selective inhibition of TYK2 could produce a unique therapeutic profile. Here, we describe the discovery of compound 9 (GLPG3667), a reversible and selective TYK2 adenosine triphosphate competitive inhibitor in development for the treatment of inflammatory and autoimmune diseases. The preclinical pharmacokinetic profile was favorable, and TYK2 selectivity was confirmed in peripheral blood mononuclear cells and whole blood assays. Dermal ear inflammation was reduced in an IL-23-induced in vivo mouse model of psoriasis. GLPG3667 also completed a phase 1b study (NCT04594928) in patients with moderate-to-severe psoriasis where clinical effect was shown within the 4 weeks of treatment and it is now in phase 2 trials for the treatment of dermatomyositis (NCT05695950) and systemic lupus erythematosus (NCT05856448).
Asunto(s)
Adenosina Trifosfato , Enfermedades Autoinmunes , Inhibidores de Proteínas Quinasas , Psoriasis , TYK2 Quinasa , Humanos , Animales , TYK2 Quinasa/antagonistas & inhibidores , TYK2 Quinasa/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/química , Ratones , Enfermedades Autoinmunes/tratamiento farmacológico , Adenosina Trifosfato/metabolismo , Psoriasis/tratamiento farmacológico , Femenino , Descubrimiento de Drogas , Masculino , Lupus Eritematoso Sistémico/tratamiento farmacológico , Relación Estructura-Actividad , AdultoRESUMEN
Autotaxin (ATX; ENPP2) produces the lipid mediator lysophosphatidic acid (LPA) that signals through disparate EDG (LPA1-3) and P2Y (LPA4-6) G protein-coupled receptors. ATX/LPA promotes several (patho)physiological processes, including in pulmonary fibrosis, thus serving as an attractive drug target. However, it remains unclear if clinical outcome depends on how different types of ATX inhibitors modulate the ATX/LPA signaling axis. Here, we show that the ATX "tunnel" is crucial for conferring key aspects of ATX/LPA signaling and dictates cellular responses independent of ATX catalytic activity, with a preference for activation of P2Y LPA receptors. The efficacy of the ATX/LPA signaling responses are abrogated more efficiently by tunnel-binding inhibitors, such as ziritaxestat (GLPG1690), compared with inhibitors that exclusively target the active site, as shown in primary lung fibroblasts and a murine model of radiation-induced pulmonary fibrosis. Our results uncover a receptor-selective signaling mechanism for ATX, implying clinical benefit for tunnel-targeting ATX inhibitors.
Asunto(s)
Fibrosis Pulmonar , Ratones , Animales , Fibrosis Pulmonar/tratamiento farmacológico , Receptores del Ácido Lisofosfatídico , Transducción de Señal , Lisofosfolípidos/química , FibroblastosRESUMEN
Innate immunity not only shapes the way epithelial barriers interpret environmental cues but also drives adaptive responses. Therefore, modulators of innate immune responses are expected to have high therapeutic potential across immune-mediated inflammatory diseases. IRAK4 is a kinase that integrates signaling downstream of receptors acting at the interface between innate and adaptive immune responses, such as Toll-like receptors (TLRs), interleukin-1R (IL-1R), and IL-18R. Because effects of IRAK4 inhibition are stimulus, cell type, and species dependent, the evaluation of the therapeutic potential of IRAK4 inhibitors requires a highly translational approach. Here, we profiled a selective IRAK4 inhibitor, GLPG2534, in an extensive panel of models of inflammatory skin diseases, translationally expanding evidence from in vitro to in vivo and from mouse to human. In vitro, IRAK4 inhibition resulted in substantial inhibition of TLR and IL-1 responses in dendritic cells, keratinocytes, granulocytes, and T cells but only weakly affected dermal fibroblast responses. Furthermore, disease activity in murine models of skin inflammation (IL-23-, IL-33-, imiquimod-, and MC903-induced) was markedly dampened by IRAK4 inhibition. Last, inhibiting IRAK4 reversed pathogenic molecular signatures in human lesional psoriasis and atopic dermatitis biopsies. Over the variety of models used, IRAK4 inhibition consistently affected central mediators of psoriasis (IL-17A) and atopic dermatitis (IL-4 and IL-13). Overall, our data highlight IRAK4 as a central player in skin inflammatory processes and demonstrate the potential of IRAK4 inhibition as a therapeutic strategy in chronic inflammatory skin diseases.
Asunto(s)
Dermatitis Atópica , Psoriasis , Humanos , Ratones , Animales , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Dermatitis Atópica/patología , Transducción de Señal , Receptores Toll-Like/uso terapéutico , Piel/patología , Psoriasis/tratamiento farmacológicoRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease. Current treatments only slow down disease progression, making new therapeutic strategies compelling. Increasing evidence suggests that S1P2 antagonists could be effective agents against fibrotic diseases. Our compound collection was mined for molecules possessing substructure features associated with S1P2 activity. The weakly potent indole hit 6 evolved into a potent phthalazone series, bearing a carboxylic acid, with the aid of a homology model. Suboptimal pharmacokinetics of a benzimidazole subseries were improved by modifications targeting potential interactions with transporters, based on concepts deriving from the extended clearance classification system (ECCS). Scaffold hopping, as a part of a chemical enablement strategy, permitted the rapid exploration of the position adjacent to the carboxylic acid. Compound 38, with good pharmacokinetics and in vitro potency, was efficacious at 10 mg/kg BID in three different in vivo mouse models of fibrotic diseases in a therapeutic setting.
Asunto(s)
Ácidos Carboxílicos/farmacología , Descubrimiento de Drogas , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Receptores de Esfingosina-1-Fosfato/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Ácidos Carboxílicos/administración & dosificación , Modelos Animales de Enfermedad , Humanos , RatonesRESUMEN
Medium-chain fatty acids (MCFAs) have been associated with anti-steatotic effects in hepatocytes. Expression of the MCFA receptor GPR84 (G protein-coupled receptor 84) is induced in immune cells under inflammatory conditions and can promote fibrogenesis. We aimed at deciphering the role of GPR84 in the pathogenesis of non-alcoholic steatohepatitis (NASH), exploring its potential as a therapeutic target. GPR84 expression is upregulated in liver from patients with non-alcoholic fatty liver disease (NAFLD), correlating with the histological degree of inflammation and fibrosis. In mouse and human, activated monocytes and neutrophils upregulate GPR84 expression. Chemotaxis of these myeloid cells by GPR84 stimulation is inhibited by two novel, small molecule GPR84 antagonists. Upon acute liver injury in mice, treatment with GPR84 antagonists significantly reduced the hepatic recruitment of neutrophils, monocytes, and monocyte-derived macrophages (MoMF). We, therefore, evaluated the therapeutic inhibition of GPR84 by these two novel antagonists in comparison to selonsertib, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, in three NASH mouse models. Pharmacological inhibition of GPR84 significantly reduced macrophage accumulation and ameliorated inflammation and fibrosis, to an extent similar to selonsertib. In conclusion, our findings support that GPR84 mediates myeloid cell infiltration in liver injury and is a promising therapeutic target in steatohepatitis and fibrosis.
RESUMEN
IL-17C is a functionally distinct member of the IL-17 family that was believed to play a role in the pathogenesis of psoriasis. Here we confirmed that IL-17C is involved in psoriasis and explored potential roles for IL-17C in atopic dermatitis (AD). An anti-IL-17C antibody, MOR106, was generated that potently and selectively binds to human and mouse IL-17C, thereby inhibiting the binding of IL-17C to its IL-17RE receptor. The antibody inhibited cutaneous inflammation in an IL-23-induced psoriatic-like skin inflammation model. In lesional skin of patients with AD, IL-17C expression levels were increased and localized to keratinocytes and infiltrating immune cells. To determine the contribution of IL-17C to AD pathogenesis, MOR106 was tested in two distinct in vivo models. In the calcipotriol-induced AD model, ear skin inflammation, TSLP, and IL-33 protein production in ears was suppressed by MOR106. Consistently, in the flaky tail strain mouse model, spontaneous development of AD-like skin inflammation was reduced by MOR106. Moreover, serum IgE levels, number of mast cells in skin and T helper type 2-related cytokines IL-4 and CCL17 in serum were all reduced. Overall, our results indicate that IL-17C is a central mediator of skin inflammation beyond psoriasis and is relevant in particular in AD.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , Dermatitis Atópica/inmunología , Interleucina-17/inmunología , Psoriasis/inmunología , Animales , Anticuerpos Neutralizantes/uso terapéutico , Biopsia , Calcitriol/administración & dosificación , Calcitriol/análogos & derivados , Calcitriol/inmunología , Células Cultivadas , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Inyecciones Intraperitoneales , Interleucina-17/antagonistas & inhibidores , Interleucina-23/administración & dosificación , Interleucina-23/inmunología , Queratinocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Cultivo Primario de Células , Psoriasis/patología , Transducción de Señal , Piel/inmunología , Piel/patologíaRESUMEN
Using immunocytochemistry, in situ hybridization and image analysis, we attempted to compare the dynamical expression of tyrosine hydroxylase (TH) and vasopressin (VP) mRNAs and proteins in the magnocellular neurons of the supraoptic nucleus in rats drinking 2% NaCl for 1, 2 and 3 weeks. Three stages in the reaction of VPergic neurons have been distinguished. The initial stage (first week) showed a synchronous activation of TH and VP mRNAs and protein expression as well as an increased number of TH-immunoreactive neurons. The next stage (second week) was characterized by a further increase in the number of TH-immunoreactive neurons. The number of VPergic neurons also increased significantly. Although the TH and VP mRNAs levels fell during the second week of osmotic stimulation, the TH content increased significantly, and the VP content remained at the same level. During the last stage (third week), TH-immunoreactive neurons increased in number and were as numerous as VP-immunoreactive neurons in intact rats. These data suggest that, finally, all the VPergic neurons begin to synthesize TH. The concentrations of VP and TH mRNAs did not change during the third week of osmotic stimulation, while the VP and TH contents increased. Thus, our study shows that there is a correlation between TH expression and VP expression and suggests similar mechanisms for the regulation of VP and TH gene expression and synthesis during long-term osmotic stimulation.