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1.
J Med Chem ; 55(2): 903-13, 2012 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-22148921

RESUMO

A substantial body of evidence supports the utility of antiangiogenesis inhibitors as a strategy to block or attenuate tumor-induced angiogenesis and inhibition of primary and metastatic tumor growth in a variety of solid and hematopoietic tumors. Given the requirement of tumors for different cytokine and growth factors at distinct stages of their growth and dissemination, optimal antiangiogenic therapy necessitates inhibition of multiple, complementary, and nonredundant angiogenic targets. 11-(2-Methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (11b, CEP-11981) is a potent orally active inhibitor of multiple targets (TIE-2, VEGF-R1, 2, and 3, and FGF-R1) having essential and nonredundant roles in tumor angiogenesis and vascular maintenance. Outlined in this article are the design strategy, synthesis, and biochemical and pharmacological profile for 11b, which completed Phase I clinical assessing safety and pharmacokinetics allowing for the initiation of proof of concept studies.


Assuntos
Inibidores da Angiogênese/síntese química , Carbazóis/síntese química , Indazóis/síntese química , Receptor TIE-2/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/farmacologia , Animais , Disponibilidade Biológica , Carbazóis/farmacocinética , Carbazóis/farmacologia , Humanos , Indazóis/farmacocinética , Indazóis/farmacologia , Macaca fascicularis , Masculino , Camundongos , Camundongos Nus , Modelos Moleculares , Neovascularização Fisiológica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor TIE-2/química , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Relação Estrutura-Atividade , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Bioorg Med Chem Lett ; 21(2): 660-3, 2011 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-21190849

RESUMO

Elaboration of the SAR around a series of 2,4-diaminopyrimidines led to a number of c-Met inhibitors in which kinase selectivity was modulated by substituents appended on the C4-aminobenzamide ring and the nature of the C2-aminoaryl ring. Further lead optimization of the C2-aminoaryl group led to benzoxazepine analogs whose pharmaceutical properties were modulated by the nature of the substituent on the benzoxazepine nitrogen. Tumor stasis (with partial regressions) were observed when an orally bioavailable analog was evaluated in a GTL-16 tumor xenograft mouse model. Subsequent PK/PD studies suggested that a metabolite contributed to the overall in vivo response.


Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirimidinas/química , Pirimidinas/uso terapêutico , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Humanos , Camundongos , Camundongos Nus , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Anticancer Agents Med Chem ; 10(1): 7-27, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20015007

RESUMO

The scatter factor/hepatocyte growth factor (HGF)-c-Met axis is involved in the malignant phenotype of various tumor types via activation of a wide range of autocrine and paracrine processes. Autocrine activation of tumor cell c-Met receptors enhances tumor cell proliferation, angiogenesis, invasion/metastasis and resistance to apoptosis and cytotoxic therapies. In addition, tumor and stroma cell-derived HGF functions as a potent angiogenic factor. Therefore, the HGF-c-Met axis is critically involved in multiple facets of normal cellular growth and homeostasis and activated in a dysregulated manner in a variety of cancers. Consequently, inhibiting the HGF-c-Met axis would be anticipated to have potent anti-tumor effects in many cancers through multiple complimentary mechanisms including increased sensitivity to current cytotoxic chemo-and radiotherapies. The acceptance of c-Met as a tractable target for cancer therapy has fostered intensive drug discovery efforts across the pharmaceutical industry. This research has led to 20 published crystal structures (with and without ligands) that revealed two distinct binding modes for ATP-competitive inhibitors: Type I ligands which assumes a U shape geometry through interactions with both hinge and activation loop residue Y1230, and Type II ligands which adopt a more extended orientation, either binding a conventional DFG-out conformation or protein conformations with varying degrees of 'DFG-out' character. Nearly a dozen small molecule c-Met inhibitors have entered human clinical trials ranging from Type I inhibitors solely selective for c-Met to Type I inhibitors with broader kinase activities to Type II inhibitors with "spectrum selective" kinase activity. The identification, profiles and properties of these clinical candidates are summarized in this review.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Animais , Antineoplásicos/química , Humanos , Ligantes , Modelos Moleculares , Proteínas Proto-Oncogênicas c-met/química
4.
Mol Cancer Ther ; 2(4): 371-82, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12700281

RESUMO

Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear zinc finger DNA-binding protein that is implicated in the repair of DNA damage. Inhibition of PARP-1 through genetic knockouts causes cells to become hypersensitive to various chemotherapeutic agents. We tested the chemopotentiating ability of the PARP-1 inhibitor, CEP-6800, when used in combination with temozolomide (TMZ), irinotecan (camptothecin or SN38), and cisplatin against U251MG glioblastoma, HT29 colon carcinoma, and Calu-6 non-small cell lung carcinoma xenografts and cell lines, respectively. Exposure of tumor cells to TMZ, camptothecin (or SN38), and cisplatin before, or in the presence of, CEP-6800 significantly increased the onset and the magnitude of DNA damage, the duration for cells to effect repair, and the onset, duration, or fraction of cells arrested at the G(2)/M boundary. In addition, in vivo biochemical efficacy studies with CEP-6800 showed that it was able to attenuate irinotecan- and TMZ-induced poly(ADP-ribose) accumulation in LoVo and HT29 xenografts, respectively. Treatment of CEP 6800 (30 mg/kg) with TMZ (17 and 34 mg/kg) resulted in 100% complete regression of U251MG tumors by day 28 versus 60% complete regression caused by TMZ alone. CEP-6800 (30 mg/kg) in combination with irinotecan (10 mg/kg) resulted in a 60% inhibition of HT29 tumor growth versus irinotecan alone by day 33. The combination therapy of cisplatin (5 mg/kg) with CEP-6800 (30 mg/kg) caused a 35% reduction in Calu-6 tumor growth versus cisplatin alone by day 28. These data suggest that CEP-6800 could be used as a chemopotentiating agent with a variety of clinically effective chemotherapeutic agents.


Assuntos
Camptotecina/análogos & derivados , Camptotecina/farmacologia , Cisplatino/farmacologia , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Antineoplásicos/farmacologia , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Divisão Celular , Linhagem Celular , Linhagem Celular Tumoral , Dano ao DNA , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Irinotecano , Cinética , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Nus , Modelos Químicos , Transplante de Neoplasias , Temozolomida , Fatores de Tempo
5.
Clin Cancer Res ; 8(6): 1924-31, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12060637

RESUMO

PURPOSE: Aberrant expression of trk receptor kinases and enhanced expression of various neurotrophins (NTs) have been implicated in the development and progression of human prostatic carcinoma and pancreatic ductal adenocarcinoma. We examined the antitumor efficacy of administration of NT neutralizing antibodies on the growth of established human prostatic carcinoma and pancreatic ductal adenocarcinoma xenografts in nude mice. EXPERIMENTAL DESIGN: In initial studies, tumor-bearing nude mice were treated with a mixture of NT antibodies [100 microg each of anti-nerve growth factor (NGF), anti-brain-derived neurotrophic factor, anti-NT-3, and anti-NT-4/5] or normal rabbit IgG (400 microg) intratumorally and peritumorally three times/week over a 15-day dosing period. In subsequent studies, tumor-bearing nude mice were treated with individual NT antibodies (100 microg), affinity-purified anti-NGF (0.1, 1.0, or 10.0 microg), or normal rabbit IgG (100 microg) using the same dosing schedule. RESULTS: Treatment with the antibody mixture inhibited significantly the growth of TSU-Pr1 and AsPC-1 xenografts as compared with IgG-treated controls (maximal inhibition of 53 and 53%, respectively), whereas this treatment caused significant regression in PC-3 xenografts. Treatment of TSU-Pr1 xenografts with either anti-NGF or anti-NT-3 resulted in maximal tumor growth inhibition of 67 and 64%, respectively, whereas anti-brain-derived neurotrophic factor and anti-NT-4/5 did not inhibit tumor growth in this tumor model. Administration of various concentrations (0.1, 1.0, or 10.0 microg) of affinity-purified anti-NGF resulted in maximal TSU-Pr1 tumor growth inhibition of 49, 62, and 66%, respectively. CONCLUSIONS: These data add further support for the therapeutic potential of disrupting trk-signaling events in select types of nonneuronal human cancers, specifically prostatic and pancreatic carcinomas.


Assuntos
Carcinoma Ductal Pancreático/prevenção & controle , Fatores de Crescimento Neural/fisiologia , Neoplasias Pancreáticas/prevenção & controle , Neoplasias da Próstata/prevenção & controle , Receptor trkA/fisiologia , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Divisão Celular , Progressão da Doença , Feminino , Humanos , Imunoglobulina G/uso terapêutico , Masculino , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Coelhos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Transplante Heterólogo
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