RESUMEN
Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and the destruction of bone and cartilage in affected joints. One of the unmet medical needs in the treatment of RA is to effectively prevent the structural destruction of joints, especially bone, which progresses because of resistance to conventional drugs that mainly have anti-inflammatory effects, and directly leads to a decline in the QOL of patients. We previously developed a novel and orally available type II kinase inhibitor of colony-stimulating factor-1 receptor (CSF1R), JTE-952. CSF1R is specifically expressed by monocytic-lineage cells, including bone-resorbing osteoclasts, and is important for promoting the differentiation and proliferation of osteoclasts. In the present study, we investigated the therapeutic effect of JTE-952 on methotrexate (MTX)-refractory joint destruction in a clinically established adjuvant-induced arthritis rat model. JTE-952 did not suppress paw swelling under inflammatory conditions, but it inhibited the destruction of joint structural components including bone and cartilage in the inflamed joints. In addition, decreased range of joint motion and mechanical hyperalgesia after disease onset were suppressed by JTE-952. These results suggest that JTE-952 is expected to prevent the progression of the structural destruction of joints and its associated effects on joint motion and pain by inhibiting CSF1/CSF1R signaling in RA pathology, which is resistant to conventional disease-modifying anti-rheumatic drugs such as MTX.
Asunto(s)
Antineoplásicos , Artritis Reumatoide , Animales , Ratas , Metotrexato/farmacología , Metotrexato/uso terapéutico , Factor Estimulante de Colonias de Macrófagos , Calidad de Vida , Artritis Reumatoide/tratamiento farmacológico , Proteínas Tirosina Quinasas ReceptorasRESUMEN
Psoriasis is an immune disorder-related inflammatory skin disease. Recent studies have suggested a contribution of T cell activation in the pathogenesis of psoriasis. Interleukin-2 (IL-2)-inducible T cell kinase (ITK) regulates T cell activation, including proliferation, and cytokine production. In this study, we investigated the effect of the topically administered selective ITK inhibitor BMS-509744 on imiquimod (IMQ)-induced psoriasis-like skin inflammation in mice. Topically administered BMS-509744 ameliorated IMQ-induced psoriasis-like skin inflammation as shown by decreased skin lesions, epidermal thickening, and cell infiltration into the dermis. These suppressive effects occurred with lower numbers of cluster of differentiation antigen-3+ (CD3+) T cells and T helper subset 17 (Th17)-related cytokine expression in IMQ-treated skin. IMQ-induced upregulation of proinflammatory cytokine expression was also inhibited by topical application of BMS-509744 in IMQ-treated skin. Our report showed for the first time that topical application of BMS-509744 ameliorated psoriasis-like skin inflammation in mice, which is likely mediated by the inhibition of T cell activation in the skin lesions.
Asunto(s)
Imiquimod/efectos adversos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Animales , Complejo CD3/metabolismo , Dermatitis/tratamiento farmacológico , Dermatitis/metabolismo , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Ratones , Ratones Endogámicos BALB C , Piel/metabolismo , Piel/patología , Células Th17/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and structural destruction of the joints. Bone damage occurs in an early stage after onset and osteoclast activation plays a substantial role in its progression. Colony stimulating factor 1 receptor (CSF1R) is a receptor protein tyrosine kinase specifically expressed in monocytic-lineage cells such as macrophages and osteoclasts. Here, we investigated the effect of JTE-952, a novel CSF1R tyrosine kinase inhibitor, on osteoclast formation in vitro and on bone destruction in a mouse model of collagen-induced arthritis. JTE-952 completely inhibited osteoclast differentiation from human monocytes, with an IC50 of 2.8 nmol/L, and reduced osteoclast formation from the synovial cells of RA patients. Detectable levels of colony stimulating factor 1 (CSF1), a ligand of CSF1R, were observed in the synovial tissues of the arthritis model, similar to those observed in the pathology of human RA. JTE-952 significantly suppressed increases in the bone destruction score, the number of tartrate-resistant-acid-phosphatase-positive cells, and the severity of arthritis in the model mice. We also examined the efficacy of JTE-952 combined with methotrexate. This combination therapy more effectively reduced the severity of bone destruction and arthritis than monotherapy with either agent alone. In summary, JTE-952 potently inhibited human osteoclast formation in vitro and suppressed bone destruction in an experimental arthritis model, especially when combined with methotrexate. These results indicate that JTE-952 should strongly inhibit bone destruction and joint inflammation in RA patients and effectively prevent the progression of the structural destruction of joints.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Azetidinas/uso terapéutico , Densidad Ósea/efectos de los fármacos , Osteoclastos/efectos de los fármacos , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Animales , Artritis Experimental/metabolismo , Artritis Experimental/patología , Azetidinas/farmacología , Densidad Ósea/fisiología , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Ratones , Ratones Endogámicos DBA , Osteoclastos/metabolismo , Osteoclastos/patología , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Membrana Sinovial/efectos de los fármacos , Membrana Sinovial/metabolismo , Membrana Sinovial/patologíaRESUMEN
Colony stimulating factor 1 (CSF1) receptor (CSF1R) is a receptor protein-tyrosine kinase specifically expressed in monocyte-lineage cells, such as monocytes and macrophages. In this study, we characterized the pharmacological properties of an azetidine compound, JTE-952 ((2S)-3-{[2-({3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]azetidine-1-yl}carbonyl)pyridin-4-yl]methoxy}propane-1,2-diol), which is a novel CSF1R tyrosine kinase inhibitor. JTE-952 potently inhibited human CSF1R kinase activity, with a half maximal inhibitory concentration of 11.1 nmol/L, and inhibited the phosphorylation of CSF1R in human macrophages and the CSF1-induced proliferation of human macrophages. It also inhibited human tropomyosin-related kinase A activity, but only at concentrations 200-fold higher than that required to inhibit the activity of CSF1R in inducing the proliferation of human macrophages. JTE-952 displayed no marked inhibitory activity against other kinases. JTE-952 potently inhibited lipopolysaccharide-induced proinflammatory cytokine production by human macrophages and in whole blood. JTE-952 (≥3 mg/kg given orally) also significantly attenuated the CSF1-induced priming of lipopolysaccharide-induced tumor necrosis factor-alpha production in mice and arthritis severity in a mouse model of collagen-induced arthritis. Taken together, these results indicate that JTE-952 is an orally available compound with potent and specific inhibitory activity against CSF1R, both in vitro and in vivo. JTE-952 is a potentially clinically useful agent for various human inflammatory diseases, including rheumatoid arthritis.
Asunto(s)
Azetidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Animales , Artritis Experimental/tratamiento farmacológico , Azetidinas/farmacocinética , Células Cultivadas , Citocinas/sangre , Citocinas/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos DBA , Ratas Endogámicas Lew , Receptor trkA/metabolismoRESUMEN
Proinflammatory cytokines and growth factors have been thought to play crucial roles in the pathology of acute myelogenous leukemia (AML) by supporting the proliferation and survival of AML cells in an autocrine and paracrine manner, although further elucidation is required. JTE-607 was originally identified as a multiple cytokine inhibitor that suppresses production of proinflammatory cytokines from lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells. Herein, we report that JTE-607 exhibits inhibitory activity on the growth of AML cell lines accompanying reduction of the proinflammatory cytokine and growth factor production. In in vitro studies, JTE-607 suppressed expression and production of cytokines, which are spontaneously up-regulated in AML cell lines. JTE-607 also abrogated proliferation of AML cells in a concentration range in which colony formation of normal bone marrow cells was not affected. The growth inhibition by JTE-607 was characterized by induction of cell-cycle arrest at the S-phase and apoptosis, accompanied by a decrease in c-Myc and increase in p21(waf1/cip1). In a leukemia model engrafted with U-937 cells, JTE-607 significantly prolonged survival in mice and reduced human cytokine mRNA levels in the bone marrow. These results suggest the usefulness of JTE-607 in therapeutic applications for patients with hypercytokinemia and aggressive AML cell proliferation.
Asunto(s)
Apoptosis/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Citocinas/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Fenilalanina/análogos & derivados , Piperazinas/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citocinas/biosíntesis , Citocinas/genética , Femenino , Humanos , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Ratones , Ratones SCID , Fenilalanina/farmacología , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
OBJECTIVE: Accumulating findings suggest that in acute myeloid leukemia (AML) patients, proinflammatory cytokines and growth factors play important roles in the proliferation and survival of AML cells in an autocrine and paracrine manner, leading to deterioration of AML. JTE-607 is a multiple cytokine inhibitor that potently suppresses production of proinflammatory cytokines. In the present study, we investigated the potency of JTE-607 as an antileukemic agent by exploiting a SCID mouse acute leukemia model. METHODS: SCID mice injected with anti-asialo-GM1 antibody were exposed to sublethal total-body irradiation at a dose of 3 Gy and then inoculated intravenously with AML cells. JTE-607 was administered using osmotic minipumps. The effects of JTE-607 on mouse survival time, human interleukin (IL)-8 levels in mouse plasma, and proportion of human CD45(+) cells in the bone marrow were studied. RESULTS: The survival time of the mice was strictly dependent on the number of U-937 cells proliferating in vivo. Administration of JTE-607 during the initial 7 days significantly prolonged survival of the mice, suggesting killing activity of JTE-607 against AML cells in vivo. Delayed administration of JTE-607 also prolonged the survival of mice bearing established leukemia with an effect comparable to the maximum tolerable dose of cytarabine. Flow cytometer analysis of bone marrow cells revealed decreased number of human CD45(+) cells. Human IL-8 level was also reduced by JTE-607. CONCLUSION: Our results indicate that JTE-607 has potential to be a new class of antileukemic drug that exerts inhibitory activities against both the proliferation and proinflammatory cytokine production of AML cells.
Asunto(s)
Citocinas/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Fenilalanina/análogos & derivados , Piperazinas/farmacología , Animales , Comunicación Autocrina/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citocinas/sangre , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Interleucina-8/sangre , Antígenos Comunes de Leucocito/sangre , Ratones , Ratones SCID , Trasplante de Neoplasias , Neoplasias Experimentales/tratamiento farmacológico , Comunicación Paracrina/efectos de los fármacos , Fenilalanina/farmacología , Fenilalanina/uso terapéutico , Piperazinas/uso terapéutico , Trasplante HeterólogoRESUMEN
JTV-803 (4-[(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)methyl]-1-(4-pyridinyl)piperidine-4-carboxylic acid monomethanesulfonate trihydrate), a specific inhibitor of factor Xa, was evaluated in a pig hemodialysis model with ligation of renal arteries. In this model, JTV-803 administered into the dialysis circuit showed an anticoagulant effect (prolongation of dialysis time) at doses of 0.3 mg/kg + 0.3, 1.0 and 3.0 mg/kg/h. The prolongation of dialysis time in the 0.3 mg/kg + 1.0 mg/kg/h JTV-803 group was comparable to that in the 15 U/kg + 7.5 U/kg/h heparin group. The plasma concentrations of JTV-803 following 0.3 mg/kg + 1.0 mg/kg/h infusion of the drug into the dialysis circuit was 500 ng/ml or less, and prothrombin time was 1.5-fold or less than the pretreatment value. JTV-803 was removed by passing the blood through a dialyzer, resulting in a clearance rate of 53.4-81.8%. After the end of dialysis, plasma concentrations of JTV-803 decreased rapidly with time. These results suggest that human factor Xa inhibitor JTV-803 may have good potential as an antithrombotic agent during hemodialysis, with lower likelihood of bleeding after the end of dialysis.