Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
JAMA Oncol ; 7(9): 1343-1350, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34236401

RESUMO

IMPORTANCE: Many cancer subtypes, including KIT-mutant gastrointestinal stromal tumors (GISTs), are driven by activating mutations in tyrosine kinases and may initially respond to kinase inhibitors but frequently relapse owing to outgrowth of heterogeneous subclones with resistance mutations. KIT inhibitors commonly used to treat GIST (eg, imatinib and sunitinib) are inactive-state (type II) inhibitors. OBJECTIVE: To assess whether combining a type II KIT inhibitor with a conformation-complementary, active-state (type I) KIT inhibitor is associated with broad mutation coverage and global disease control. DESIGN, SETTING, AND PARTICIPANTS: A highly selective type I inhibitor of KIT, PLX9486, was tested in a 2-part phase 1b/2a trial. Part 1 (dose escalation) evaluated PLX9486 monotherapy in patients with solid tumors. Part 2e (extension) evaluated PLX9486-sunitinib combination in patients with GIST. Patients were enrolled from March 2015 through February 2019; data analysis was performed from May 2020 through July 2020. INTERVENTIONS: Participants received 250, 350, 500, and 1000 mg of PLX9486 alone (part 1) or 500 and 1000 mg of PLX9486 together with 25 or 37.5 mg of sunitinib (part 2e) continuously in 28-day dosing cycles until disease progression, treatment discontinuation, or withdrawal. MAIN OUTCOMES AND MEASURES: Pharmacokinetics, safety, and tumor responses were assessed. Clinical efficacy end points (progression-free survival and clinical benefit rate) were supplemented with longitudinal monitoring of KIT mutations in circulating tumor DNA. RESULTS: A total of 39 PLX9486-naive patients (median age, 57 years [range, 39-79 years]; 22 men [56.4%]; 35 [89.7%] with refractory GIST) were enrolled in the dose escalation and extension parts. The recommended phase 2 dose of PLX9486 was 1000 mg daily. At this dose, PLX9486 could be safely combined with 25 or 37.5 mg daily of sunitinib continuously. Patients with GIST who received PLX9486 at a dose of 500 mg or less, at the recommended phase 2 dose, and with sunitinib had median (95% CI) progression-free survivals of 1.74 (1.54-1.84), 5.75 (0.99-11.0), and 12.1 (1.34-NA) months and clinical benefit rates (95% CI) of 14% (0%-58%), 50% (21%-79%), and 80% (52%-96%), respectively. CONCLUSIONS AND RELEVANCE: In this phase 1b/2a nonrandomized clinical trial, type I and type II KIT inhibitors PLX9486 and sunitinib were safely coadministered at the recommended dose of both single agents in patients with refractory GIST. Results suggest that cotargeting 2 complementary conformational states of the same kinase was associated with clinical benefit with an acceptable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02401815.


Assuntos
Tumores do Estroma Gastrointestinal , Mesilato de Imatinib , Inibidores de Proteínas Quinases , Sunitinibe , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Sunitinibe/efeitos adversos
2.
Nat Commun ; 10(1): 3758, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434879

RESUMO

Many risk genes for the development of Alzheimer's disease (AD) are exclusively or highly expressed in myeloid cells. Microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for their survival. We designed and synthesized a highly selective brain-penetrant CSF1R inhibitor (PLX5622) allowing for extended and specific microglial elimination, preceding and during pathology development. We find that in the 5xFAD mouse model of AD, plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia. Instead, Aß deposits in cortical blood vessels reminiscent of cerebral amyloid angiopathy. Altered gene expression in the 5xFAD hippocampus is also reversed by the absence of microglia. Transcriptional analyses of the residual plaque-forming microglia show they exhibit a disease-associated microglia profile. Collectively, we describe the structure, formulation, and efficacy of PLX5622, which allows for sustained microglial depletion and identify roles of microglia in initiating plaque pathogenesis.


Assuntos
Doença de Alzheimer/metabolismo , Microglia/metabolismo , Compostos Orgânicos/farmacologia , Placa Amiloide/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Doença de Alzheimer/genética , Animais , Comportamento Animal , Encéfalo/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hipocampo/metabolismo , Humanos , Memória , Camundongos , Camundongos Transgênicos , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Transcriptoma
3.
Cancer Discov ; 8(4): 458-477, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29386193

RESUMO

Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or de novo expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers.Significance: To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. Cancer Discov; 8(4); 458-77. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 371.


Assuntos
Regulação Leucêmica da Expressão Gênica , Isoxazóis/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Proteínas Nucleares/genética , Piridinas/uso terapêutico , Pirróis/uso terapêutico , Transdução de Sinais , Fatores de Transcrição/genética , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Perfilação da Expressão Gênica , Humanos , Isoxazóis/farmacologia , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/fisiopatologia , Camundongos , Camundongos SCID , Proteínas Nucleares/metabolismo , Piridinas/farmacologia , Pirróis/farmacologia , Fatores de Transcrição/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Nature ; 526(7574): 583-6, 2015 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-26466569

RESUMO

Oncogenic activation of BRAF fuels cancer growth by constitutively promoting RAS-independent mitogen-activated protein kinase (MAPK) pathway signalling. Accordingly, RAF inhibitors have brought substantially improved personalized treatment of metastatic melanoma. However, these targeted agents have also revealed an unexpected consequence: stimulated growth of certain cancers. Structurally diverse ATP-competitive RAF inhibitors can either inhibit or paradoxically activate the MAPK pathway, depending whether activation is by BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. Here we have identified next-generation RAF inhibitors (dubbed 'paradox breakers') that suppress mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation. In cells that express the same HRAS mutation prevalent in squamous tumours from patients treated with RAF inhibitors, the first-generation RAF inhibitor vemurafenib stimulated in vitro and in vivo growth and induced expression of MAPK pathway response genes; by contrast the paradox breakers PLX7904 and PLX8394 had no effect. Paradox breakers also overcame several known mechanisms of resistance to first-generation RAF inhibitors. Dissociating MAPK pathway inhibition from paradoxical activation might yield both improved safety and more durable efficacy than first-generation RAF inhibitors, a concept currently undergoing human clinical evaluation with PLX8394.


Assuntos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Feminino , Genes ras/genética , Compostos Heterocíclicos com 2 Anéis/efeitos adversos , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Indóis/efeitos adversos , Indóis/farmacologia , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Modelos Biológicos , Mutação/genética , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia , Vemurafenib
5.
Cancer Discov ; 5(6): 668-79, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25847190

RESUMO

UNLABELLED: Tyrosine kinase domain mutations are a common cause of acquired clinical resistance to tyrosine kinase inhibitors (TKI) used to treat cancer, including the FLT3 inhibitor quizartinib. Mutation of kinase "gatekeeper" residues, which control access to an allosteric pocket adjacent to the ATP-binding site, has been frequently implicated in TKI resistance. The molecular underpinnings of gatekeeper mutation-mediated resistance are incompletely understood. We report the first cocrystal structure of FLT3 with the TKI quizartinib, which demonstrates that quizartinib binding relies on essential edge-to-face aromatic interactions with the gatekeeper F691 residue, and F830 within the highly conserved Asp-Phe-Gly motif in the activation loop. This reliance makes quizartinib critically vulnerable to gatekeeper and activation loop substitutions while minimizing the impact of mutations elsewhere. Moreover, we identify PLX3397, a novel FLT3 inhibitor that retains activity against the F691L mutant due to a binding mode that depends less vitally on specific interactions with the gatekeeper position. SIGNIFICANCE: We report the first cocrystal structure of FLT3 with a kinase inhibitor, elucidating the structural mechanism of resistance due to the gatekeeper F691L mutation. PLX3397 is a novel FLT3 inhibitor with in vitro activity against this mutation but is vulnerable to kinase domain mutations in the FLT3 activation loop.


Assuntos
Aminopiridinas/farmacologia , Benzotiazóis/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Mutação , Compostos de Fenilureia/farmacologia , Pirróis/farmacologia , Tirosina Quinase 3 Semelhante a fms/genética , Aminopiridinas/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzotiazóis/química , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Xenoenxertos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Modelos Moleculares , Conformação Molecular , Compostos de Fenilureia/química , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas/genética , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirróis/química , Recidiva , Relação Estrutura-Atividade , Tirosina Quinase 3 Semelhante a fms/química
6.
Proc Natl Acad Sci U S A ; 110(14): 5689-94, 2013 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-23493555

RESUMO

Inflammation and cancer, two therapeutic areas historically addressed by separate drug discovery efforts, are now coupled in treatment approaches by a growing understanding of the dynamic molecular dialogues between immune and cancer cells. Agents that target specific compartments of the immune system, therefore, not only bring new disease modifying modalities to inflammatory diseases, but also offer a new avenue to cancer therapy by disrupting immune components of the microenvironment that foster tumor growth, progression, immune evasion, and treatment resistance. McDonough feline sarcoma viral (v-fms) oncogene homolog (FMS) and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) are two hematopoietic cell surface receptors that regulate the development and function of macrophages and mast cells, respectively. We disclose a highly specific dual FMS and KIT kinase inhibitor developed from a multifaceted chemical scaffold. As expected, this inhibitor blocks the activation of macrophages, osteoclasts, and mast cells controlled by these two receptors. More importantly, the dual FMS and KIT inhibition profile has translated into a combination of benefits in preclinical disease models of inflammation and cancer.


Assuntos
Aminopiridinas/farmacologia , Inflamação/tratamento farmacológico , Modelos Moleculares , Metástase Neoplásica/tratamento farmacológico , Proteína Oncogênica gp140(v-fms)/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Pirróis/farmacologia , Aminopiridinas/síntese química , Aminopiridinas/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Cromatografia de Afinidade , Cristalização , Escherichia coli , Células Endoteliais da Veia Umbilical Humana , Humanos , Indóis , Macrófagos/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Estrutura Molecular , Mutação de Sentido Incorreto/genética , Proteína Oncogênica gp140(v-fms)/química , Proteína Oncogênica gp140(v-fms)/genética , Osteoclastos/efeitos dos fármacos , Conformação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-kit/química , Proteínas Proto-Oncogênicas c-kit/genética , Pirróis/síntese química , Pirróis/química , Células Sf9 , Spodoptera
7.
Nature ; 467(7315): 596-9, 2010 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-20823850

RESUMO

B-RAF is the most frequently mutated protein kinase in human cancers. The finding that oncogenic mutations in BRAF are common in melanoma, followed by the demonstration that these tumours are dependent on the RAF/MEK/ERK pathway, offered hope that inhibition of B-RAF kinase activity could benefit melanoma patients. Herein, we describe the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic B-RAF kinase activity. Preclinical experiments demonstrated that PLX4032 selectively blocked the RAF/MEK/ERK pathway in BRAF mutant cells and caused regression of BRAF mutant xenografts. Toxicology studies confirmed a wide safety margin consistent with the high degree of selectivity, enabling Phase 1 clinical trials using a crystalline formulation of PLX4032 (ref. 5). In a subset of melanoma patients, pathway inhibition was monitored in paired biopsy specimens collected before treatment initiation and following two weeks of treatment. This analysis revealed substantial inhibition of ERK phosphorylation, yet clinical evaluation did not show tumour regressions. At higher drug exposures afforded by a new amorphous drug formulation, greater than 80% inhibition of ERK phosphorylation in the tumours of patients correlated with clinical response. Indeed, the Phase 1 clinical data revealed a remarkably high 81% response rate in metastatic melanoma patients treated at an oral dose of 960 mg twice daily. These data demonstrate that BRAF-mutant melanomas are highly dependent on B-RAF kinase activity.


Assuntos
Indóis/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/enzimologia , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Alelos , Animais , Cães , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/química , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macaca fascicularis , Melanoma/genética , Melanoma/patologia , Modelos Moleculares , Proteínas Mutantes/antagonistas & inibidores , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Metástase Neoplásica , Fosforilação/efeitos dos fármacos , Tomografia por Emissão de Pósitrons , Proteínas Proto-Oncogênicas B-raf/química , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Ratos , Especificidade por Substrato , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/química , Vemurafenib , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Med Chem ; 51(19): 6173-87, 2008 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-18788731

RESUMO

A novel series of symmetrical ureas of [(7-amino(2-naphthyl))sulfonyl]phenylamines were designed, synthesized, and tested for their ability to increase glucose transport in mouse 3T3-L1 adipocytes, a surrogate readout for activation of the insulin receptor (IR) tyrosine kinase (IRTK). A structure-activity relationship was established that indicated glucose transport activity was dependent on the presence of two acidic functionalities, two sulfonamide linkages, and a central urea or 2-imidazolidinone core. Compound 30 was identified as a potent and selective IRTK activator. At low concentrations, 30 was able to increase the tyrosine phosphorylation of the IR stimulated by submaximal insulin. At higher concentrations, 30 was able to increase tyrosine the phosphorylation levels of the IR in the absence of insulin. When administered intraperitoneally (ip) and orally (po), 30 improved glucose tolerance in hypoinsulinemic, streptozotocin-treated rats. These data provide pharmacological validation that small molecule IRTK activators represent a potential new class of antidiabetic agents.


Assuntos
Compostos de Anilina/farmacologia , Desenho de Fármacos , Receptor de Insulina/efeitos dos fármacos , Sulfonamidas/farmacologia , Ureia/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Administração Oral , Compostos de Anilina/síntese química , Compostos de Anilina/química , Animais , Sítios de Ligação , Glicemia/análise , Células Cultivadas , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Fibroblastos/efeitos dos fármacos , Teste de Tolerância a Glucose , Injeções Intraperitoneais , Masculino , Camundongos , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Estreptozocina/administração & dosagem , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Ureia/análogos & derivados , Ureia/química
10.
J Cell Biochem ; 92(6): 1234-45, 2004 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-15258906

RESUMO

Protease inhibitor (PI) therapy for the treatment of patients infected with human immunodeficiency virus is frequently associated with insulin resistance and diabetic complications. These adverse effects of PI treatment result to a large extent from their inhibition of insulin-stimulated glucose transport. Insulin receptor (IR) activators that enhance the insulin signaling pathway could be effective in treating this resistance. However, there are no agents reported that reverse inhibition of insulin action by PIs. Herein, we describe the effects of TLK19781. This compound is a non-peptide, small molecule, activator of the IR. We now report in cultured cells, made insulin resistant HIV by PI treatment, that TLK19781 both increased the content of insulin-stimulated GLUT4 at the plasma membrane, and enhanced insulin-stimulated glucose transport. In addition, oral administration of TLK19781 with the PI, indinavir improved glucose tolerance in rats made insulin resistant. These results suggest, therefore, that IR activators such as TLK19781 may be useful in treating the insulin resistance associated with PIs.


Assuntos
Inibidores da Protease de HIV/farmacologia , Indinavir/farmacologia , Resistência à Insulina , Naftalenos/farmacologia , Receptor de Insulina/agonistas , Ácidos Sulfanílicos/farmacologia , Células 3T3-L1 , Adipócitos/metabolismo , Administração Oral , Animais , Transporte Biológico , Receptores ErbB/metabolismo , Glucose/metabolismo , Teste de Tolerância a Glucose , Transportador de Glucose Tipo 4 , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/efeitos adversos , Técnicas In Vitro , Indinavir/administração & dosagem , Indinavir/efeitos adversos , Camundongos , Proteínas de Transporte de Monossacarídeos/metabolismo , Proteínas Musculares/metabolismo , Naftalenos/administração & dosagem , Fosforilação , Ratos , Receptor de Insulina/metabolismo , Ácidos Sulfanílicos/administração & dosagem
11.
J Biol Chem ; 277(46): 43565-71, 2002 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-12213804

RESUMO

In type 2 diabetes mellitus, impaired insulin signaling leads to hyperglycemia and other metabolic abnormalities. TLK19780, a non-peptide small molecule, is a new member of a novel class of anti-diabetic agents that function as activators of the insulin receptor (IR) beta-subunit tyrosine kinase. In HTC-IR cells, 20 microm TLK19780 enhanced maximal insulin-stimulated IR autophosphorylation 2-fold and increased insulin sensitivity 2-3-fold. In contrast, TLK19780 did not potentiate the action of insulin-like growth factor-1, indicating the selectivity of TLK19780 toward the IR. The predominant effect of TLK19780 was to increase the number of IR that underwent autophosphorylation. Kinetic studies indicated that TLK19780 acted very rapidly, with a maximal effect observed 2 min after addition to insulin-stimulated cells. In 3T3-L1 adipocytes, 5 microm TLK19780 enhanced insulin-stimulated glucose transport, increasing both the sensitivity and maximal responsiveness to insulin. These studies indicate that at low micromolar levels small IR activator molecules can enhance insulin action in various cultured cells and suggest that this effect is mediated by increasing the number of IR that are tyrosine-phosphorylated in response to insulin. These studies suggest that these types of molecules could be developed to treat type 2 diabetes and other clinical conditions associated with insulin resistance.


Assuntos
Receptor de Insulina/metabolismo , Receptor de Insulina/fisiologia , Células 3T3 , Adipócitos/metabolismo , Animais , Transporte Biológico , Western Blotting , Células CHO , Carcinoma Hepatocelular/metabolismo , Células Cultivadas , Cricetinae , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Ensaio de Imunoadsorção Enzimática , Glucose/metabolismo , Cinética , Camundongos , Modelos Químicos , Fosforilação , Ratos , Ácidos Sulfanílicos/farmacologia , Fatores de Tempo , Tirosina/metabolismo , Ureia/análogos & derivados , Ureia/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...