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In this article we address the relevance of rare diseases and their peculiarities with respect to pain therapy. Towards this end, four rare diseases (hemophilia, Morbus Fabry, dermatomyositis, and facioscapulohumeral dystrophy (FSHD)) will be presented and fundamental aspects of their pain therapies described. The diseases were chosen to showcase a pain therapy based on the WHO-step-by-step plan (hemophilia), a complex but established pain therapy (M. Fabry), and two less well established, individually adapted pain therapies (dermatomyositis, FSHD).
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Distrofia Muscular Facioescapuloumeral , Manejo da Dor , Doenças Raras , Humanos , Distrofia Muscular Facioescapuloumeral/terapia , Doenças Raras/complicaçõesRESUMO
Sickle cell disease is associated with numerous symptoms and complications. Acute painful crisis is the most characteristic manifestation of the disease. In addition, many patients report chronic pain. As both acute and chronic pain severely diminish quality of life, adequate pain management is crucial. Recommendations for the treatment of acute painful crises are based on the World Health Organization analgesic ladder, which has been developed for cancer-related pain. Chronic pain can be treated with basic long-acting opioids and on-demand short-acting opioids. If patients show signs of neuropathic pain, administration of anticonvulsants, antidepressants or possibly ketamine should be considered.
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Anemia Falciforme , Manejo da Dor , Analgésicos , Analgésicos Opioides/uso terapêutico , Anemia Falciforme/complicações , Humanos , Medição da Dor , Qualidade de VidaRESUMO
Farnesoid X receptor (FXR) agonists are emerging as important potential therapeutics for the treatment of nonalcoholic steatohepatitis (NASH) patients, as they exert positive effects on multiple aspects of the disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular inflammation, hepatic injury, and fibrosis. While there are currently no approved therapies for NASH, the bile acid-derived FXR agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in clinical studies. Previously, we described the discovery of tropifexor (LJN452), the most potent non-bile acid FXR agonist currently in clinical investigation. Here, we report the discovery of a novel chemical series of non-bile acid FXR agonists based on a tricyclic dihydrochromenopyrazole core from which emerged nidufexor (LMB763), a compound with partial FXR agonistic activity in vitro and FXR-dependent gene modulation in vivo. Nidufexor has advanced to Phase 2 human clinical trials in patients with NASH and diabetic nephropathy.
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Benzotiazóis/uso terapêutico , Ácido Quenodesoxicólico/análogos & derivados , Dieta Hiperlipídica/efeitos adversos , Isoxazóis/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Benzotiazóis/química , Ácido Quenodesoxicólico/química , Ácido Quenodesoxicólico/uso terapêutico , Cães , Humanos , Isoxazóis/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Estrutura Terciária de Proteína , Ratos , Resultado do TratamentoRESUMO
This corrects the article DOI: 10.1038/nrd.2018.97.
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Danger signals are a hallmark of many common inflammatory diseases, and these stimuli can function to activate the cytosolic innate immune signalling receptor NLRP3 (NOD-, LRR- and pyrin domain-containing 3). Once activated, NLRP3 nucleates the assembly of an inflammasome, leading to caspase 1-mediated proteolytic activation of the interleukin-1ß (IL-1ß) family of cytokines, and induces an inflammatory, pyroptotic cell death. Pharmacological inhibition of NLRP3 activation results in potent therapeutic effects in a wide variety of rodent models of inflammatory diseases, effects that are mirrored by genetic ablation of NLRP3. Although these findings highlight the potential of NLRP3 as a drug target, an understanding of NLRP3 structure and activation mechanisms is incomplete, which has hampered the discovery and development of novel therapeutics against this target. Here, we review recent advances in our understanding of NLRP3 activation and regulation, highlight the evolving landscape of NLRP3 modulators and discuss opportunities for pharmacologically targeting NLRP3 with novel small molecules.
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The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonists that introduce a bicyclic nortropine-substituted benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole scaffold. Herein, we report the discovery of 1 (tropifexor, LJN452), a novel and highly potent agonist of FXR. Potent in vivo activity was demonstrated in rodent PD models by measuring the induction of FXR target genes in various tissues. Tropifexor has advanced into phase 2 human clinical trials in patients with NASH and PBC.
Assuntos
Benzotiazóis/farmacologia , Colestase/tratamento farmacológico , Isoxazóis/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/agonistas , Administração Oral , Animais , Benzotiazóis/uso terapêutico , Disponibilidade Biológica , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Isoxazóis/uso terapêutico , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Piperidinas/química , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Relação Estrutura-Atividade , Triglicerídeos/sangueRESUMO
OBJECTIVES: Wnt signalling has been implicated in activating a fibrogenic programme in fibroblasts in systemic sclerosis (SSc). Porcupine is an O-acyltransferase required for secretion of Wnt proteins in mammals. Here, we aimed to evaluate the antifibrotic effects of pharmacological inhibition of porcupine in preclinical models of SSc. METHODS: The porcupine inhibitor GNF6231 was evaluated in the mouse models of bleomycin-induced skin fibrosis, in tight-skin-1 mice, in murine sclerodermatous chronic-graft-versus-host disease (cGvHD) and in fibrosis induced by a constitutively active transforming growth factor-ß-receptor I. RESULTS: Treatment with pharmacologically relevant and well-tolerated doses of GNF6231 inhibited the activation of Wnt signalling in fibrotic murine skin. GNF6231 ameliorated skin fibrosis in all four models. Treatment with GNF6231 also reduced pulmonary fibrosis associated with murine cGvHD. Most importantly, GNF6231 prevented progression of fibrosis and showed evidence of reversal of established fibrosis. CONCLUSIONS: These data suggest that targeting the Wnt pathway through inhibition of porcupine provides a potential therapeutic approach to fibrosis in SSc. This is of particular interest, as a close analogue of GNF6231 has already demonstrated robust pathway inhibition in humans and could be available for clinical trials.
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Aminopiridinas/uso terapêutico , Proteínas de Membrana/antagonistas & inibidores , Piperazinas/uso terapêutico , Esclerodermia Localizada/prevenção & controle , Escleroderma Sistêmico/prevenção & controle , Pele/patologia , Via de Sinalização Wnt/efeitos dos fármacos , Aciltransferases , Aminopiridinas/farmacologia , Animais , Bleomicina , Modelos Animais de Doenças , Progressão da Doença , Feminino , Fibrose , Doença Enxerto-Hospedeiro/complicações , Camundongos Endogâmicos BALB C , Piperazinas/farmacologia , Proteínas Serina-Treonina Quinases/genética , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/prevenção & controle , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/genética , Esclerodermia Localizada/etiologia , Esclerodermia Localizada/metabolismo , Escleroderma Sistêmico/induzido quimicamente , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Pele/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Blockade of aberrant Wnt signaling is an attractive therapeutic approach in multiple cancers. We developed and performed a cellular high-throughput screen for inhibitors of Wnt secretion and pathway activation. A lead structure (GNF-1331) was identified from the screen. Further studies identified the molecular target of GNF-1331 as Porcupine, a membrane bound O-acyl transferase. Structure-activity relationship studies led to the discovery of a novel series of potent and selective Porcupine inhibitors. Compound 19, GNF-6231, demonstrated excellent pathway inhibition and induced robust antitumor efficacy in a mouse MMTV-WNT1 xenograft tumor model.
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Insufficient pancreatic ß-cell mass or function results in diabetes mellitus. While significant progress has been made in regulating insulin secretion from ß-cells in diabetic patients, no pharmacological agents have been described that increase ß-cell replication in humans. Here we report aminopyrazine compounds that stimulate robust ß-cell proliferation in adult primary islets, most likely as a result of combined inhibition of DYRK1A and GSK3B. Aminopyrazine-treated human islets retain functionality in vitro and after transplantation into diabetic mice. Oral dosing of these compounds in diabetic mice induces ß-cell proliferation, increases ß-cell mass and insulin content, and improves glycaemic control. Biochemical, genetic and cell biology data point to Dyrk1a as the key molecular target. This study supports the feasibility of treating diabetes with an oral therapy to restore ß-cell mass, and highlights a tractable pathway for future drug discovery efforts.
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Proliferação de Células , Quinase 3 da Glicogênio Sintase/genética , Células Secretoras de Insulina/citologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Animais , Divisão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Regulação para Baixo/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/enzimologia , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Piridazinas/farmacologia , Quinases DyrkRESUMO
Emerging approaches to treat immune disorders target positive regulatory kinases downstream of antigen receptors with small molecule inhibitors. Here we provide evidence for an alternative approach in which inhibition of the negative regulatory inositol kinase Itpkb in mature T lymphocytes results in enhanced intracellular calcium levels following antigen receptor activation leading to T cell death. Using Itpkb conditional knockout mice and LMW Itpkb inhibitors these studies reveal that Itpkb through its product IP4 inhibits the Orai1/Stim1 calcium channel on lymphocytes. Pharmacological inhibition or genetic deletion of Itpkb results in elevated intracellular Ca2+ and induction of FasL and Bim resulting in T cell apoptosis. Deletion of Itpkb or treatment with Itpkb inhibitors blocks T-cell dependent antibody responses in vivo and prevents T cell driven arthritis in rats. These data identify Itpkb as an essential mediator of T cell activation and suggest Itpkb inhibition as a novel approach to treat autoimmune disease.
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Doenças Autoimunes/enzimologia , Doenças Autoimunes/terapia , Linfócitos T CD4-Positivos/metabolismo , Sinalização do Cálcio , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Doenças Autoimunes/patologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Canais de Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Fosfatos de Inositol/metabolismo , Células Jurkat , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína ORAI1 , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Ratos Endogâmicos LewRESUMO
Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs.
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Systematic SAR optimization of the GPR119 agonist lead 1, derived from an internal HTS campaign, led to compound 29. Compound 29 displays significantly improved in vitro activity and oral exposure, leading to GLP1 elevation in acutely dosed mice and reduced glucose excursion in an OGTT study in rats at doses ⩾10 mg/kg.
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Pirimidinas/síntese química , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Animais , Descoberta de Drogas , Camundongos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
Screening hit 5 was identified in a biochemical screen for GPR119 agonists. Compound 5 was structurally novel, displayed modest biochemical activity and no oral exposure, but was structurally distinct from typical GPR119 agonist scaffolds. Systematic optimization led to compound 36 with significantly improved in vitro activity and oral exposure, to elevate GLP1 acutely in an in vivo mouse model at a dose of 10mg/kg.
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Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Pirazóis/química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
Activation of the G-protein coupled receptor (GPCR) Takeda G-protein receptor 5 (TGR5), also known as G-protein bile acid receptor 1 (GPBAR1), has been shown to play a key role in pathways associated with diabetes, metabolic syndrome, and autoimmune disease. Nipecotamide 5 was identified as an attractive starting point after a high-throughput screen (HTS) for receptor agonists. A comprehensive hit-to-lead effort culminated in the discovery of 45h as a potent, selective, and bioavailable TGR5 agonist to test in preclinical metabolic disease models. In genetically obese mice (ob/ob), 45h was as effective as a dipeptidyl peptidase-4 (DPP-4) inhibitor at reducing peak glucose levels in an acute oral glucose tolerance test (OGTT), but this effect was lost upon chronic dosing.
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Hipoglicemiantes/síntese química , Piperazinas/síntese química , Receptores Acoplados a Proteínas G/agonistas , Administração Oral , Animais , Disponibilidade Biológica , Descoberta de Drogas , Peptídeo 1 Semelhante ao Glucagon/análise , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Piperazinas/farmacologia , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Sudden pain-free impairment of vision often occurs due to acute occlusions of retinal blood vessels. Retinal vascular occlusion can be distinguished into the more frequent venous and to a lesser degree arterial events but mixed pictures also occur. OBJECTIVES: Summary of the current literature regarding interdisciplinary diagnosis and therapy of retinal blood vessel occlusions. MATERIALS AND METHODS: Selective literature review considering clinically relevant cardiovascular and hemostaseological aspects. RESULTS: The anatomical localization of the occlusion by the ophthalmologist can give important indications for further medical diagnostic and therapeutic decisions. Arterial occlusions are mostly caused by thromboembolisms and the source should be identified and treated. Venous occlusions are mostly due to local processes with a prothrombotic background or venous stasis associated with arterial hypertension. Prognostically, the localization, extent and duration of retinal ischemia are decisive factors. CONCLUSIONS: Vascular ocular occlusions are frequently secondary to internal disorders and therefore pose an interdisciplinary challenge.
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Equipe de Assistência ao Paciente , Oclusão da Veia Retiniana/diagnóstico , Oclusão da Veia Retiniana/terapia , Tromboembolia/diagnóstico , Tromboembolia/terapia , Transtornos da Visão/prevenção & controle , Cardiologia/tendências , Hematologia/tendências , Humanos , Oftalmologia/tendências , Oclusão da Veia Retiniana/complicações , Tromboembolia/complicações , Transtornos da Visão/diagnóstico , Transtornos da Visão/etiologiaRESUMO
The purpose of this study was to assess the frequency, severity, and clinical associations of dural ectasia (DE) in Loeys-Dietz syndrome (LDS). Database analysis of three German metropolitan regions identified 30 patients with LDS and TGFBR1 mutation in 6 and a TGFBR2 mutation in 24 individuals (17 men; mean age: 31 ± 19 years), as well as 60 age and sex-matched control patients with Marfan syndrome carrying a FBN1 mutation. DE was present in 22 patients with LDS (73%), and it related to skeletal score points (p = 0.008), non-skeletal score points (p < 0.001), and to the presence of ≥7 systemic score points (p = 0.010). Similarly, the severity of DE was related to body height (p = 0.010) and non-skeletal score points (p = 0.004). Frequency (p = 0.131) and severity of DE (p = 0.567) was similar in LDS and Marfan syndrome. DE is a manifestation of LDS that occurs with similar frequency and severity as in Marfan syndrome. Severity of DE may serve as a marker of the overall connective tissue disease severity. LDS may be considered in patients with DE.
Assuntos
Dilatação Patológica/genética , Síndrome de Loeys-Dietz/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Adolescente , Adulto , Idoso , Estatura , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Síndrome de Loeys-Dietz/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Síndrome de Marfan/genética , Síndrome de Marfan/fisiopatologia , Pessoa de Meia-Idade , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptor do Fator de Crescimento Transformador beta Tipo II , Adulto JovemRESUMO
Wnt signaling is one of the key oncogenic pathways in multiple cancers, and targeting this pathway is an attractive therapeutic approach. However, therapeutic success has been limited because of the lack of therapeutic agents for targets in the Wnt pathway and the lack of a defined patient population that would be sensitive to a Wnt inhibitor. We developed a screen for small molecules that block Wnt secretion. This effort led to the discovery of LGK974, a potent and specific small-molecule Porcupine (PORCN) inhibitor. PORCN is a membrane-bound O-acyltransferase that is required for and dedicated to palmitoylation of Wnt ligands, a necessary step in the processing of Wnt ligand secretion. We show that LGK974 potently inhibits Wnt signaling in vitro and in vivo, including reduction of the Wnt-dependent LRP6 phosphorylation and the expression of Wnt target genes, such as AXIN2. LGK974 is potent and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV-Wnt1 and a human head and neck squamous cell carcinoma model (HN30). We also show that head and neck cancer cell lines with loss-of-function mutations in the Notch signaling pathway have a high response rate to LGK974. Together, these findings provide both a strategy and tools for targeting Wnt-driven cancers through the inhibition of PORCN.
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Proteínas de Membrana/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Pirazinas/farmacologia , Piridinas/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Aciltransferases , Animais , Proteína Axina/antagonistas & inibidores , Western Blotting , Linhagem Celular Tumoral , Clonagem Molecular , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Mutagênese , Fosforilação/efeitos dos fármacos , Pirazinas/uso terapêutico , Piridinas/uso terapêutico , Ensaio Radioligante , Ratos , Receptores Notch/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
In this study we examined the serum activity of lactate dehydrogenase (LDH) and its isoenzyme patterns in 28 calves of a lowland black spotted breed and its crossbreeds at the age of 2-6 months suffering from clinically noticeable manifested respiratory diseases--bronchopneumonia (BRD Group). As a control group we used 35 clinically healthy calves of the same age, breed and nutrition (Healthy Group). The sick calves did not show clinical signs or pathological lesions on other organ systems. The results found in sick calves showed a significantly higher total activity of LDH than in clinically healthy animals (P < 0.01). The mean activity of LDH was 2012 U/I in healthy calves and in calves with respiratory diseases 2529 U/1. The differences in all LDH isoenzyme patterns between both groups of animals were significant (P < 0.001) and in calves with respiratory diseases are characterized by a marked increase of the LDH 1 fraction and a decrease in the proportion of the other four LDH isoenzymes. Our results differ from those observed and presented in respiratory diseases in human medicine or in sheep. The explanation for the obtained results in calves and the determination of their diagnostic significance needs further studies and investigations using more animals with various severity of clinical signs and pathological changes, including analysis and determination of lactate dehydrogenase isoenzyme patterns in healthy and affected cattle lung tissue.
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Broncopneumonia/veterinária , Doenças dos Bovinos/enzimologia , Regulação Enzimológica da Expressão Gênica/fisiologia , L-Lactato Desidrogenase/sangue , Animais , Broncopneumonia/sangue , Broncopneumonia/metabolismo , Bovinos , Doenças dos Bovinos/sangue , Doenças dos Bovinos/metabolismo , Isoenzimas/genética , Isoenzimas/metabolismo , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/metabolismoRESUMO
The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.
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Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Sulfonas/síntese química , Quinase do Linfoma Anaplásico , Animais , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Cães , Humanos , Macaca fascicularis , Masculino , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Sulfonas/farmacocinética , Sulfonas/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Neurotrophins and their receptors (TRKs) play key roles in the development of the nervous system and the maintenance of the neural network. Accumulating evidence points to their role in malignant transformations, chemotaxis, metastasis, and survival signaling and may contribute to the pathogenesis of a variety of tumors of both neural and non-neural origin. By screening the GNF kinase collection, a series of novel oxindole inhibitors of TRKs were identified. Optimization led to the identification of GNF-5837 (22), a potent, selective, and orally bioavailable pan-TRK inhibitor that inhibited tumor growth in a mouse xenograft model derived from RIE cells expressing both TRKA and NGF. The properties of 22 make it a good tool for the elucidation of TRK biology in cancer and other nononcology indications.