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1.
PLoS One ; 14(3): e0212670, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30913212

RESUMO

Immunotherapy has fundamentally changed the landscape of cancer treatment. Despite the encouraging results with the checkpoint modulators, response rates vary widely across tumor types, with a majority of patients exhibiting either primary resistance without a significant initial response to treatment or acquired resistance with subsequent disease progression. Hematopoietic progenitor kinase 1 (HPK1) is predominantly expressed in hematopoietic cell linages and serves as a negative regulator in T cells and dendritic cells (DC). While HPK1 gene knockout (KO) studies suggest its role in anti-tumor immune responses, the involvement of kinase activity and thereof its therapeutic potential remain unknown. To investigate the potential of pharmacological intervention using inhibitors of HPK1, we generated HPK1 kinase dead (KD) mice which carry a single loss-of-function point mutation in the kinase domain and interrogated the role of kinase activity in immune cells in the context of suppressive factors or the tumor microenvironment (TME). Our data provide novel findings that HKP1 kinase activity is critical in conferring suppressive functions of HPK1 in a wide range of immune cells including CD4+, CD8+, DC, NK to Tregs, and inactivation of kinase domain was sufficient to elicit robust anti-tumor immune responses. These data support the concept that an HPK1 small molecule kinase inhibitor could serve as a novel agent to provide additional benefit in combination with existing immunotherapies, particularly to overcome resistance to current treatment regimens.


Assuntos
Imunidade Celular , Vigilância Imunológica , Linfócitos/imunologia , Neoplasias Experimentais/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Microambiente Tumoral/imunologia , Animais , Linhagem Celular Tumoral , Linfócitos/patologia , Camundongos , Camundongos Mutantes , Neoplasias Experimentais/genética , Mutação Puntual , Proteínas Serina-Treonina Quinases/genética , Microambiente Tumoral/genética
2.
Proc Natl Acad Sci U S A ; 115(13): 3249-3254, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29531094

RESUMO

For cancer cells to survive and proliferate, they must escape normal immune destruction. One mechanism by which this is accomplished is through immune suppression effected by up-regulation of indoleamine 2,3-dioxygenase (IDO1), a heme enzyme that catalyzes the oxidation of tryptophan to N-formylkynurenine. On deformylation, kynurenine and downstream metabolites suppress T cell function. The importance of this immunosuppressive mechanism has spurred intense interest in the development of clinical IDO1 inhibitors. Herein, we describe the mechanism by which a class of compounds effectively and specifically inhibits IDO1 by targeting its apo-form. We show that the in vitro kinetics of inhibition coincide with an unusually high rate of intrinsic enzyme-heme dissociation, especially in the ferric form. X-ray crystal structures of the inhibitor-enzyme complexes show that heme is displaced from the enzyme and blocked from rebinding by these compounds. The results reveal that apo-IDO1 serves as a unique target for inhibition and that heme lability plays an important role in posttranslational regulation.


Assuntos
Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/química , Apoproteínas/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Células HeLa , Heme/metabolismo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Concentração Inibidora 50 , Mioglobina/química
3.
Bioorg Med Chem Lett ; 28(4): 732-736, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29398543

RESUMO

A novel series of o-phenylenediamine-based inhibitors of indoleamine 2,3-dioxygenase (IDO) has been identified. IDO is a heme-containing enzyme, overexpressed in the tumor microenvironment of many cancers, which can contribute to the suppression of the host immune system. Synthetic modifications to a previously described diarylether series resulted in an additional degree of molecular diversity which was exploited to afford compounds that demonstrated significant potency in the HeLa human cervical cancer IDO1 assay. .


Assuntos
Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Fenilenodiaminas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Células HeLa , Humanos , Microssomos Hepáticos/metabolismo , Fenilenodiaminas/síntese química , Fenilenodiaminas/química , Fenilenodiaminas/metabolismo , Relação Estrutura-Atividade
6.
Exp Cell Res ; 338(2): 251-60, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26302264

RESUMO

Cellular levels of inhibitor of apoptosis (IAP) proteins are elevated in multiple human cancers and their activities often play a part in promoting cancer cell survival by blocking apoptotic pathways, controlling signal transduction pathways and contributing to resistance. These proteins function through interactions of their BIR (baculoviral IAP repeat) protein domains with pathway components and these interactions are endogenously antagonized by Smac/Diablo (second mitochondrial activator of caspases/direct IAP binding protein with low isoelectric point). This report describes development of synthetic smac mimetics (SM) and compares their binding, antiproliferative and anti-tumor activities. All dimeric antagonists inhibit in vitro smac tetrapeptide binding to recombinant IAP proteins, rescue IAP-bound caspase-3 activity and show anti-proliferative activity against human A875 melanoma cells. One heterodimeric SM, SM3, binds tightly to IAP proteins in vitro and slowly dissociates (greater than two hours) from these protein complexes compared to the other antagonists. In addition, in vitro SM anti-proliferation potency is influenced by ABCB1 transporter (ATP-binding cassette, sub-family B; MDR1, P-gp) activities and one antagonist, SM5, does not appear to be an ABCB1 efflux pump substrate. All dimeric smac mimetics inhibit the growth of human melanoma A875 tumors implanted in athymic mice at well-tolerated doses. One antagonist, SM4, shows broad spectrum in vivo anti-tumor activity and modulates known pharmacodynamic markers of IAP antagonism. These data taken together demonstrate the range of diverse dimeric IAP antagonist activities and supports their potential as anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Caspase 3/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Mitocondriais/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Biomimética/métodos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Células HCT116 , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína/efeitos dos fármacos
7.
ACS Med Chem Lett ; 6(5): 523-7, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-26005526

RESUMO

Structure-activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides identified highly potent inhibitors of γ-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation.

8.
Bioorg Med Chem Lett ; 25(9): 1905-9, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25857941
9.
Cancer Immunol Immunother ; 62(9): 1533-45, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23873089

RESUMO

Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) binding agent, has proven to be an effective monotherapy for metastatic melanoma and has shown antitumor activity in trials when administered with other therapeutic agents. We hypothesized that the combination of ipilimumab with chemotherapeutic agents, such as ixabepilone, paclitaxel, etoposide, and gemcitabine, may produce therapeutic synergy based on distinct but complementary mechanisms of action for each drug and unique cellular targets. This concept was investigated using a mouse homolog of ipilimumab in preclinical murine tumor models, including SA1N fibrosarcoma, EMT-6 mammary carcinoma, M109 lung carcinoma, and CT-26 colon carcinoma. Results of CTLA-4 blockade in combination with one of various chemotherapeutic agents demonstrate that synergy occurs in settings where either agent alone was not effective in inducing tumor regression. Furthermore, when combined with CTLA-4 blockade, ixabepilone, etoposide, and gemcitabine elicited prolonged antitumor effects in some murine models with induction of a memory immune response. Future investigations are warranted to determine which specific chemo-immunotherapy combinations, if any, will produce synergistic antitumor effects in the clinical setting.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Neoplasias Experimentais/tratamento farmacológico , Animais , Antígeno CTLA-4/imunologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Epotilonas/farmacologia , Etoposídeo/farmacologia , Feminino , Ipilimumab , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/imunologia
10.
Bioorg Med Chem Lett ; 23(14): 4107-11, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23747226

RESUMO

The design, synthesis and characterization of a phosphonate inhibitor of N-acetylneuraminate-9-phosphate phosphatase (HDHD4) is described. Compound 3, where the substrate C-9 oxygen was replaced with a nonlabile CH2 group, inhibits HDHD4 with a binding affinity (IC50 11µM) in the range of the native substrate Neu5Ac-9-P (compound 1, Km 47µM). Combined SAR, modeling and NMR studies are consistent with the phosphonate group in inhibitor 3 forming a stable complex with native Mg(2+). In addition to this key interaction, the C-1 carboxylate of the sugar interacts with a cluster of basic residues, K141, R104 and R72. Comparative NMR studies of compounds 3 and 1 with Ca(2+) and Mg(2+) are indicative of a highly dynamic process in the active site for the HDHD4/Mg(2+)/3 complex. Possible explanations for this observation are discussed.


Assuntos
Desenho de Drogas , Inibidores Enzimáticos/síntese química , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Ácidos Siálicos/síntese química , Fosfatos Açúcares/síntese química , Animais , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Cinética , Espectroscopia de Ressonância Magnética , Simulação de Acoplamento Molecular , Monoéster Fosfórico Hidrolases/metabolismo , Estrutura Terciária de Proteína , Ratos , Ácidos Siálicos/química , Ácidos Siálicos/metabolismo , Fosfatos Açúcares/química , Fosfatos Açúcares/metabolismo
11.
Clin Cancer Res ; 17(12): 4031-41, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21531814

RESUMO

PURPOSE: The extensive involvement of the HER kinases in epithelial cancer suggests that kinase inhibitors targeting this receptor family have the potential for broad spectrum antitumor activity. BMS-690514 potently inhibits all three HER kinases, and the VEGF receptor kinases. This report summarizes data from biochemical and cellular pharmacology studies, as well as antitumor activity of BMS-690514. EXPERIMENTAL DESIGN: The potency and selectivity of BMS-690514 was evaluated by using an extensive array of enzymatic and binding assays, as well as cellular assays that measure proliferation and receptor signaling. Antitumor activity was evaluated by using multiple xenograft models that depend on HER kinase signaling. The antiangiogenic properties of BMS-690514 were assessed in a matrigel plug assay, and effect on tumor blood flow was measured by dynamic contrast-enhanced MRI. RESULTS: BMS-690514 is a potent and selective inhibitor of epidermal growth factor receptor (EGFR), HER2, and HER4, as well as the VEGF receptor kinases. It inhibits proliferation of tumor cells with potency that correlates with inhibition of receptor signaling, and induces apoptosis in lung tumor cells that have an activating mutation in EGFR. Antitumor activity was observed with BMS-690514 at multiple doses that are well tolerated in mice. There was evidence of suppression of tumor angiogenesis and endothelial function by BMS-690514, which may contribute to its efficacy. CONCLUSIONS: By combining inhibition of two receptor kinase families, BMS-690524 is a novel targeted agent that disrupts signaling in the tumor and its vasculature.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Neoplasias/enzimologia , Piperidinas/farmacologia , Pirróis/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Triazinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/irrigação sanguínea , Neovascularização Patológica/enzimologia , Receptor ErbB-2/metabolismo , Fluxo Sanguíneo Regional/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Mol Cancer Ther ; 9(2): 369-78, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20103604

RESUMO

Tumor angiogenesis is a complex and tightly regulated network mediated by various proangiogenic factors. The fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) family of growth factors, and associated tyrosine kinase receptors have a major influence in tumor growth and dissemination and may work synergistically to promote angiogenesis. Brivanib alaninate is the orally active prodrug of brivanib, a selective dual inhibitor of FGF and VEGF signaling. Here, we show that brivanib demonstrates antitumor activity in a broad range of xenograft models over multiple dose levels and that brivanib alaninate shows dose-dependent efficacy equivalent to brivanib in L2987 human tumor xenografts. Brivanib alaninate (107 mg/kg) reduced tumor cell proliferation as determined by a 76% reduction in Ki-67 staining and reduced tumor vascular density as determined by a 76% reduction in anti-CD34 endothelial cell staining. Furthermore, Matrigel plug assays in athymic mice showed that brivanib alaninate inhibited angiogenesis driven by VEGF or basic FGF alone, or combined. Dynamic contrast-enhanced magnetic resonance imaging, used to assess the effects of brivanib alaninate on tumor microcirculation, showed a marked decrease in gadopentetate dimeglumine contrast agent uptake at 107 mg/kg dose, with a reduction in area under the plasma concentration-time curve from time 0 to 60 minutes at 24 and 48 hours of 54% and 64%, respectively. These results show that brivanib alaninate is an effective antitumor agent in preclinical models across a range of doses, and that efficacy is accompanied by changes in cellular and vascular activities.


Assuntos
Pirróis/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Triazinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Alanina/análogos & derivados , Animais , Antígenos CD34/biossíntese , Linhagem Celular Tumoral , Colágeno/química , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Humanos , Laminina/química , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Proteoglicanas/química , Transdução de Sinais , Fatores de Tempo
13.
J Med Chem ; 52(5): 1251-4, 2009 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-19260711

RESUMO

Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.


Assuntos
Aminopiridinas/síntese química , Antineoplásicos/síntese química , Di-Hidropiridinas/síntese química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridonas/síntese química , Administração Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Di-Hidropiridinas/farmacocinética , Di-Hidropiridinas/farmacologia , Cães , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Piridonas/farmacocinética , Piridonas/farmacologia , Ratos , Solubilidade , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Mol Cancer Ther ; 8(2): 275-81, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19174552

RESUMO

The discovery of the antineoplastic agent paclitaxel and its unique activity as a microtubule-stabilizing agent resulted in dramatic improvements in the treatment of breast, ovarian, and non-small cell lung cancers. Despite the potent antitumor activity of taxanes such as paclitaxel, efficacy of these agents has been limited by development of taxane-resistant tumors in patients. This review describes, with some historical context, our successful efforts to discover a next-generation microtubule-stabilizing agent for the treatment of cancer. In collaboration with the Gesellschaft für Biotechnologische Forschung, we evaluated the epothilones, originally isolated from the myxobacterium Sorangium cellulosum, as potential anticancer agents. Experiments performed at Bristol-Myers Squibb confirmed the ability of these agents to induce tubulin polymerization, cell cycle arrest, and apoptosis. Epothilones A and B showed potent cytotoxic activity toward paclitaxel-sensitive and paclitaxel-resistant cells expressing P-glycoprotein or mutant tubulin. Because the parent epothilones were subject to inactivation via esterase cleavage, we used semisynthetic approaches to prepare analogues without this liability. BMS-247550 (ixabepilone), the lactam analogue of epothilone B, showed increased metabolic stability, potent tubulin polymerization activity, and retained activity against paclitaxel-resistant lines. Based on its shown efficacy in clinical trials, ixabepilone was approved by the Food and Drug Administration in 2007 for treatment of drug-resistant/refractory metastatic or locally advanced breast cancer.


Assuntos
Descoberta de Drogas/história , Epotilonas/história , Epotilonas/farmacologia , Animais , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Estabilidade de Medicamentos , Epotilonas/química , História do Século XX , História do Século XXI , Humanos , Lactamas/química
15.
J Med Chem ; 51(17): 5330-41, 2008 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-18690676

RESUMO

Conformationally constrained 2-pyridone analogue 2 is a potent Met kinase inhibitor with an IC50 value of 1.8 nM. Further SAR of the 2-pyridone based inhibitors of Met kinase led to potent 4-pyridone and pyridine N-oxide inhibitors such as 3 and 4. The X-ray crystallographic data of the inhibitor 2 bound to the ATP binding site of Met kinase protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues showed potent antiproliferative activities against the Met dependent GTL-16 gastric carcinoma cell line. Compound 2 also inhibited Flt-3 and VEGFR-2 kinases with IC50 values of 4 and 27 nM, respectively. It possesses a favorable pharmacokinetic profile in mice and demonstrates significant in vivo antitumor activity in the GTL-16 human gastric carcinoma xenograft model.


Assuntos
Antineoplásicos/síntese química , Fosfotransferases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Piridonas/farmacologia , Receptores de Fatores de Crescimento/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-met , Piridonas/síntese química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores
16.
Bioorg Med Chem Lett ; 18(11): 3224-9, 2008 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-18479916

RESUMO

A series of acylurea analogs derived from pyrrolopyridine and aminopyridine scaffolds were identified as potent inhibitors of Met kinase activity. The SAR at various positions of the two kinase scaffolds was investigated. These studies led to the discovery of compounds 3b and 20b, which demonstrated favorable pharmacokinetic properties in mice and significant antitumor activity in a human gastric carcinoma xenograft model.


Assuntos
Aminopiridinas/síntese química , Aminopiridinas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirróis/síntese química , Pirróis/farmacologia , Ureia/síntese química , Ureia/farmacologia , Aminopiridinas/química , Animais , Humanos , Camundongos , Inibidores de Proteínas Quinases/química , Pirróis/química , Neoplasias Gástricas/induzido quimicamente , Neoplasias Gástricas/patologia , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Bioorg Med Chem Lett ; 18(9): 2985-9, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18395443

RESUMO

We report herein a series of substituted N-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amines as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. Through structure-activity relationship studies, biochemical potency, pharmacokinetics, and kinase selectivity were optimized to afford BMS-645737 (13), a compound with good preclinical in vivo activity against human tumor xenograft models.


Assuntos
Inibidores da Angiogênese/farmacologia , Desenho de Drogas , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirróis/farmacologia , Triazinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/síntese química , Animais , Linhagem Celular , Inibidores do Citocromo P-450 CYP3A , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Pirróis/síntese química , Relação Estrutura-Atividade , Triazinas/síntese química , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Med Chem ; 51(6): 1976-80, 2008 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-18288793

RESUMO

A series of amino acid ester prodrugs of the dual VEGFR-2/FGFR-1 kinase inhibitor 1 (BMS-540215) was prepared in an effort to improve the aqueous solubility and oral bioavailability of the parent compound. These prodrugs were evaluated for their ability to liberate parent drug 1 in in vitro and in vivo systems. The l-alanine prodrug 8 (also known as brivanib alaninate/BMS-582664) was selected as a development candidate and is presently in phase II clinical trials.


Assuntos
Carcinoma/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Pró-Fármacos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Triazinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Alanina/análogos & derivados , Animais , Disponibilidade Biológica , Proliferação de Células/efeitos dos fármacos , Ensaios Clínicos Fase II como Assunto , Desenho de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Intestinos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Camundongos , Microssomos/efeitos dos fármacos , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirróis/síntese química , Pirróis/química , Solubilidade , Estereoisomerismo , Triazinas/síntese química , Triazinas/química , Água/química , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Bioorg Med Chem Lett ; 18(6): 1945-51, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18289854

RESUMO

An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compounds with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallography revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner.


Assuntos
Inibidores Enzimáticos/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirróis/química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Triazinas/química , Animais , Células CACO-2/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Glutationa Transferase/antagonistas & inibidores , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Conformação Proteica , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-met , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento/metabolismo , Neoplasias Gástricas/sangue , Neoplasias Gástricas/enzimologia , Relação Estrutura-Atividade
20.
Bioorg Med Chem Lett ; 18(4): 1354-8, 2008 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-18221875

RESUMO

Introduction of the 2,4-difluoro-5-(cyclopropylcarbamoyl)phenylamino group at the C-4 position of the pyrrolo[2,1-f][1,2,4] triazine scaffold led to the discovery of a novel sub-series of inhibitors of VEGFR-2 kinase activity. Subsequent SAR studies on the 1,3,5-oxadiazole ring appended to the C-6 position of this new sub-family of pyrrolotriazines resulted in the identification of low nanomolar inhibitors of VEGFR-2. Antitumor efficacy was observed with compound 37 against L2987 human lung carcinoma xenografts in athymic mice.


Assuntos
Ciclopropanos/química , Ciclopropanos/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Triazinas/química , Triazinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Ciclopropanos/síntese química , Inibidores das Enzimas do Citocromo P-450 , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Nus , Oxidiazóis/síntese química , Oxidiazóis/química , Oxidiazóis/farmacologia , Inibidores de Proteínas Quinases/química , Pirróis/síntese química , Pirróis/química , Pirróis/farmacologia , Relação Estrutura-Atividade , Triazinas/síntese química , Ensaios Antitumorais Modelo de Xenoenxerto
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