RESUMO
The design and enzyme activities of a novel class of imidazo[2,1-b]thiazoles is presented.
Assuntos
Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Tiazóis/farmacologia , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Tiazóis/químicaRESUMO
Emerging clinical and pre-clinical data indicate that both insulin-like growth factor receptor (IGF-IR) and members of the epidermal growth factor (EGF) family of receptor tyrosine kinases (RTKs) exhibit significant cross-talk in human cancers. Therefore, a small molecule that successfully inhibits the signaling of both classes of oncogenic kinases might provide an attractive agent for chemotherapeutic use. Herein, we disclose the structure activity relationships that led to the synthesis and biological characterization of 14, a novel small molecule inhibitor of both IGF-IR and members of the epidermal growth factor family of RTKs.
Assuntos
Antineoplásicos/síntese química , Química Farmacêutica/métodos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores de Somatomedina/antagonistas & inibidores , Receptores de Somatomedina/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Dimerização , Desenho de Fármacos , Humanos , Pulmão/metabolismo , Modelos Químicos , Neoplasias/metabolismo , Fosforilação , Pirimidinas/química , Receptores Proteína Tirosina Quinases/química , Transdução de SinaisRESUMO
The insulin-like growth factor-1 receptor (IGF-1R) and ErbB family of receptors are receptor tyrosine kinases that play important roles in cancer. Lack of response and resistance to therapies targeting ErbB receptors occur and are often associated with activation of the IGF-1R pathway. Combinations of agents that inhibit IGF-1R and ErbB receptors have been shown to synergistically block cancer cell proliferation and xenograft tumor growth. To determine the mechanism by which targeting both IGF-1R and ErbB receptors causes synergistic effects on cell growth and survival, we investigated the effects of combinations of selective IGF-1R and ErbB kinase inhibitors on proliferative and apoptotic signaling. We identified A431 squamous cell carcinoma cells as most sensitive to combinations of ErbB and IGF-1R inhibitors. The inhibitor combinations resulted in not only blockade of A431 cell proliferation, but also induced apoptosis, which was not seen with either agent alone. Upon examining phosphorylation states and expression levels of proteins in the IGF-1R and ErbB signaling pathways, we found a correlation between the ability of combinations to inhibit proliferation and to decrease levels of phosphorylated Akt and cyclin D1. In addition, the massive cell death induced by combined IGF-1R/ErbB inhibition was associated with Mcl-1 reduction and Bax activation. Thus, targeting both IGF-1R and ErbB receptors simultaneously results in cell cycle arrest and apoptosis through combined effects on Akt, cyclin D1, and Bax activation.
Assuntos
Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Proteínas Oncogênicas v-erbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclina D , Ciclinas/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides , Transplante de Neoplasias , Neoplasias/enzimologia , Proteínas Oncogênicas v-erbB/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transplante Heterólogo , Proteína X Associada a bcl-2/metabolismoRESUMO
A high throughput screen of Abbott's compound repository revealed that the pyrazolo[3,4-d]pyrimidine class of kinase inhibitors possessed moderate potency for IGF-IR, a promising target for cancer chemotherapy. The synthesis and subsequent optimization of this class of compounds led to the discovery of 14, a compound that possesses in vivo IGF-IR inhibitory activity.
Assuntos
Pirazóis/síntese química , Pirazóis/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores de Somatomedina/antagonistas & inibidores , Administração Oral , Animais , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Injeções Intravenosas , Camundongos , Fosforilação , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
Methionine aminopeptidase-2 (MetAP2) is a novel target for cancer therapy. As part of an effort to discover orally active reversible inhibitors of MetAP2, a series of anthranilic acid sulfonamides with micromolar affinities for human MetAP2 were identified using affinity selection by mass spectrometry (ASMS) screening. These micromolar hits were rapidly improved to nanomolar leads on the basis of insights from protein crystallography; however, the compounds displayed extensive binding to human serum albumin and had limited activity in cellular assays. Modifications based on structural information on the binding of lead compounds to both MetAP2 and domain III of albumin allowed the identification of compounds with significant improvements in both parameters, which showed good cellular activity in both proliferation and methionine processing assays.
Assuntos
Aminopeptidases/química , Antineoplásicos/síntese química , Metaloendopeptidases/química , Albumina Sérica/química , Sulfonamidas/síntese química , ortoaminobenzoatos/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Técnicas In Vitro , Espectrometria de Massas , Metionina/metabolismo , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Estrutura Terciária de Proteína , Ratos , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacologiaRESUMO
We have screened molecules for inhibition of MetAP2 as a novel approach toward antiangiogenesis and anticancer therapy using affinity selection/mass spectrometry (ASMS) employing MetAP2 loaded with Mn(2+) as the active site metal. After a series of anthranilic acid sulfonamides with micromolar affinities was identified, chemistry efforts were initiated. The micromolar hits were quickly improved to potent nanomolar inhibitors by chemical modifications guided by insights from X-ray crystallography.
Assuntos
Aminopeptidases/antagonistas & inibidores , Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Glicoproteínas/antagonistas & inibidores , Sulfonamidas/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Manganês/química , Espectrometria de Massas/métodos , Metionil Aminopeptidases , Modelos Moleculares , Estrutura Molecular , Sensibilidade e Especificidade , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
The synthesis and biological activities of rapamycin (I) analogs modified at the C-40 position are reported. Emphasis placed on compounds that potentially have an improved safety profile on account of their shorter in vivo half-life when compared with rapamycin.
Assuntos
Antirreumáticos/química , Antirreumáticos/farmacocinética , Artrite Reumatoide/metabolismo , Sirolimo/análogos & derivados , Animais , Antirreumáticos/toxicidade , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Masculino , Radiografia , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-DawleyRESUMO
Substituted 3-amino-2-hydroxyamides and related hydroxyamides and acylhydrazines were identified as inhibitors of human methionine aminopeptidase-2 (MetAP2). Examination of substituents through parallel synthesis and iterative structure-based design allowed the identification of potent inhibitors with good selectivity against MetAP1. Diacylhydrazine 3t (A-357300) was identified as an analogue displaying inhibition of methionine processing and cellular proliferation in human microvascular endothelial cells (HMVEC).
Assuntos
Amidas/química , Amidas/farmacologia , Aminopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Metaloendopeptidases/antagonistas & inibidores , Sítios de Ligação/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Humanos , Metionina/efeitos dos fármacos , Modelos Biológicos , Modelos Moleculares , Estrutura MolecularRESUMO
Methionine aminopeptidase (MetAP)-2 has been suggested as a novel target for cancer therapy because the anticancer agent TNP-470 irreversibly inactivates the catalytic activity of this enzyme. However, the importance of MetAP2 in cell growth and tumor progression was uncertain because previous data were based on the chemically reactive TNP-470. Here we show that a rationally designed reversible MetAP2 inhibitor, A-357300, suppresses tumor growth preclinically without the toxicities observed with TNP-470. We have synthesized this bestatin-type MetAP2 inhibitor with the aid of crystal structures of the enzyme-inhibitor complexes and parallel synthesis. A-357300 induces cytostasis by cell cycle arrest at the G(1) phase selectively in endothelial cells and in a subset of tumor cells, but not in most primary cells of nonendothelial type. A-357300 inhibits angiogenesis both in vitro and in vivo and shows potent antitumor efficacy in carcinoma, sarcoma, and neuroblastoma murine models. These data affirm that MetAP2 plays a pivotal role in cell growth and establish that reversible MetAP2 inhibitors are promising novel cancer therapeutic agents.