RESUMO
Therapeutic development of a targeted agent involves a series of decisions over additional activities that may be ignored, eliminated or pursued. This paper details the concurrent application of two methods that provide a spectrum of information about the biological activity of a compound: biochemical profiling on a large panel of kinase assays and transcriptional profiling of mRNA responses. Our mRNA profiling studies used a full dose range, identifying subsets of transcriptional responses with differing EC(50)s which may reflect distinct targets. Profiling data allowed prioritization for validation in xenograft models, generated testable hypotheses for active compounds, and informed decisions on the general utility of the series.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/genética , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Quinase 9 Dependente de Ciclina/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Receptor IGF Tipo 1/genética , TriagemRESUMO
A series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one were synthesized to modulate CYP3A4 inhibition and improve aqueous solubility of our prototypical compound BMS-536924 (1), while maintaining potent IGF-1R inhibitory activity. Structure-activity and structure-solubility studies led to the identification of BMS-577098 (27), which demonstrates oral in vivo efficacy in animal models. The improvement was achieved by replacing morpholine with more polar bio-isoster piperazine and modulating the basicity of distal nitrogen with appropriate substitutions.
Assuntos
Benzimidazóis/química , Piperazinas/química , Inibidores de Proteínas Quinases/química , Piridonas/química , Administração Oral , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Humanos , Camundongos , Camundongos Nus , Piperazinas/síntese química , Piperazinas/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Piridonas/síntese química , Piridonas/farmacocinética , Piridonas/farmacologia , Ratos , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The SAR of PXR transactivation by 3-(benzimidazol-2-yl)-pyridine-2-one based ATP competitive inhibitors of Insulin-like Growth Factor 1 Receptor kinase (IGF-1R) is discussed. Compounds without PXR transactivation, with in vivo antitumor activity, reduced protein binding and improved oral exposure are presented.
Assuntos
Antineoplásicos/química , Benzimidazóis/química , Inibidores de Proteínas Quinases/química , Receptor IGF Tipo 1/antagonistas & inibidores , Receptores de Esteroides/genética , Ativação Transcricional , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Linhagem Celular Tumoral , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Humanos , Camundongos , Camundongos Nus , Receptor de Pregnano X , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Receptor IGF Tipo 1/metabolismo , Receptores de Esteroides/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases (Ki, <2 nmol/L). It is currently in phase I development for the treatment of a variety of human cancers. BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines (IC50, 5-365 nmol/L); the compound caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of the sub-G1 fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active in vivo in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a minimum effective dose of as low as 6.25 mg/kg dosed orally daily. Combination studies with BMS-754807 have been done on multiple human tumor cell types and showed in vitro synergies (combination index, <1.0) when combined with cytotoxic, hormonal, and targeted agents. The combination of cetuximab and BMS-754807 in vivo, at multiple dose levels, resulted in improved clinical outcome over single agent treatment. These data show that BMS-754807 is an efficacious, orally active growth factor 1 receptor/insulin receptor family-targeted kinase inhibitor that may act in combination with a wide array of established anticancer agents.
Assuntos
Pirazóis/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor de Insulina/antagonistas & inibidores , Triazinas/farmacologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Western Blotting , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cetuximab , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Poli(ADP-Ribose) Polimerases/metabolismo , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Triazinas/administração & dosagem , Triazinas/farmacocinética , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Structure-activity relationships in a series of 4-[1H-indazol-5-ylamino]pyrrolo[2,1-f][1,2,4]triazine-6-carbamates identified dual human epidermal growth factor receptor (HER)1/HER2 kinase inhibitors with excellent biochemical potency and kinase selectivity. On the basis of its favorable pharmacokinetic profile and robust in vivo activity in HER1 and HER2 driven tumor models, 13 (BMS-599626) was selected as a clinical candidate for treatment of solid tumors.
Assuntos
Antineoplásicos/síntese química , Carbamatos/síntese química , Receptores ErbB/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Triazinas/síntese química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Carbamatos/farmacocinética , Carbamatos/farmacologia , Linhagem Celular Tumoral , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Macaca fascicularis , Camundongos , Transplante de Neoplasias , Estereoisomerismo , Relação Estrutura-Atividade , Transplante Heterólogo , Triazinas/farmacocinética , Triazinas/farmacologiaRESUMO
We previously reported that 1 (BMS-536924), a benzimidazole inhibitor of the insulin-like growth factor-1 receptor, had demonstrated in vivo antitumor activity. This lead compound was found to have potent CYP3A4 inhibition, CYP3A4 induction mediated by PXR transactivation, poor aqueous solubility, and high plasma protein binding. Herein we disclose the evolution of this chemotype to address these issues. This effort led to 10 (BMS-695735), which exhibits improved ADME properties, a low risk for drug-drug interactions, and in vivo efficacy in multiple xenograft models.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacologia , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Piridonas/administração & dosagem , Piridonas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/química , Benzimidazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Transplante de Neoplasias , Receptor de Pregnano X , Inibidores de Proteínas Quinases/química , Piridonas/química , Receptores de Esteroides/efeitos dos fármacos , Receptores de Esteroides/metabolismo , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
3-(Benzimidazol-2-yl)-pyridine-2-one-based ATP competitive inhibitors of Insulin-like Growth Factor 1 Kinase (IGF-IR) were optimized for reduced Cyp3A4 inhibition and improved oral exposure. The use of malonate as methyl anion synthon via S(N)Ar reaction and double decarboxylation under mild conditions is demonstrated.
Assuntos
Benzimidazóis/farmacologia , Inibidores do Citocromo P-450 CYP3A , Receptor IGF Tipo 1/antagonistas & inibidores , Trifosfato de Adenosina/química , Administração Oral , Área Sob a Curva , Química Farmacêutica/métodos , Citocromo P-450 CYP3A/química , Desenho de Fármacos , Flúor/química , Humanos , Concentração Inibidora 50 , Modelos Químicos , Nitrogênio/química , Receptor IGF Tipo 1/química , Somatomedinas/química , Timidina/químicaRESUMO
A series of IGF-1R inhibitors is disclosed, wherein the (m-chlorophenyl)ethanol side chain of BMS-536924 (1) is replaced with a series of 2-(1H-imidazol-4-yl)ethanamine and 2-(1H-pyrazol-1-yl)ethanamine side chains. Some analogs show improved IGF-1R potency and oral exposure. Analogs from both series, 16a and 17f, show in vivo activity comparable to 1 in our constitutively activated IGF-1R Sal tumor model. This may be the due to the improved protein binding in human and mouse serum for imidazole 16a and the excellent oral exposure of pyrazole 17f.
Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Piridonas/química , Piridonas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Humanos , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Ligação Proteica , Soro , Relação Estrutura-AtividadeRESUMO
Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a 5-((4-aminopiperidin-1-yl)methyl) solubilizing group were found to be superior to analogs with previously reported C-5 solubilizing groups. New synthetic methodology was developed for the parallel synthesis of C-4 analogs with the new solubilizing group. Interesting new leads were evaluated in tumor xenograft models and the C-4 aminofluorobenzylindazole, 1c, was found to exhibit the best antitumor activity. It is hypothesized that this solubilizing group extends into the ribose-phosphate portion of the ATP binding pocket and enhances the binding affinity of the inhibitor.
Assuntos
Química Farmacêutica/métodos , Receptores ErbB/química , Neoplasias/tratamento farmacológico , Piperidinas/síntese química , Pirróis/síntese química , Receptor ErbB-2/química , Triazinas/síntese química , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Insetos , Modelos Químicos , Transplante de Neoplasias , Piperidinas/química , Piperidinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Triazinas/química , Triazinas/farmacologiaRESUMO
Novel C-5 aminomethyl pyrrolotriazines were prepared and optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The homopiperazine, 1p, emerged as a key lead and it showed promising oral efficacy in EGFR and dual EGFR/HER2 driven human tumor xenograft models. It is hypothesized that the C-5 homopiperazine side chain binds in the ribose-phosphate portion of the ATP binding pocket.
Assuntos
Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Metilaminas/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirróis/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Triazinas/farmacologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Metilaminas/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Transplante de Neoplasias , Pirróis/química , Relação Estrutura-Atividade , Triazinas/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Novel C-5 substituted pyrrolotriazines were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The lead compound exhibited promising oral efficacy in both EGFR and HER2 driven human tumor xenograft models. It is hypothesized that its C-5 morpholine side chain binds in the ribose phosphate portion of the ATP binding pocket.
Assuntos
Química Farmacêutica/métodos , Receptores ErbB/antagonistas & inibidores , Pirróis/síntese química , Receptor ErbB-2/antagonistas & inibidores , Triazinas/síntese química , Trifosfato de Adenosina/química , Animais , Células CACO-2 , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Transplante de Neoplasias , Fosfatos/química , Pirróis/farmacologia , Ribose/química , Triazinas/farmacologiaRESUMO
Compound 3 (BMS-536924), a novel small-molecule inhibitor of the insulin-like growth factor receptor kinase with equal potency against the insulin receptor is described. The in vitro and in vivo biological activity of this interesting compound is also reported.
Assuntos
Antineoplásicos/síntese química , Benzimidazóis/síntese química , Piridinas/síntese química , Piridonas/síntese química , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Haplorrinos , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Transplante de Neoplasias , Piridinas/química , Piridinas/farmacologia , Piridonas/química , Piridonas/farmacologia , Ratos , Receptor de Insulina/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A novel series of dual EGFR and HER2 inhibitors based on the pyrrolo[2,1-f][1,2,4]triazine nucleus is described. A general route toward their synthesis, which enables functionalization at multiple sites, has been developed. Biological evaluation in enzymatic and cell-based assays has identified a series of C-6 carbamates with potent biochemical and cellular activities.
Assuntos
Receptores ErbB/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Sítios de Ligação , Carbamatos/síntese química , Carbamatos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Modelos Moleculares , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/farmacologiaRESUMO
A series of fluoroglycosylated fluoroindolocarbazoles was examined with respect to their topoisomerase I activity, cytotoxicity, and selectivity. The lead clinical candidate from this series, BMS-250749, displays broad spectrum antitumor activity superior to CPT-11 against some preclinical xenograft models, including curative antitumor activity against Lewis lung carcinoma.
Assuntos
Antineoplásicos/síntese química , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Carbazóis/síntese química , Glucosídeos/síntese química , Indóis/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Glucosídeos/química , Glucosídeos/farmacologia , Humanos , Técnicas In Vitro , Indóis/química , Indóis/farmacologia , Irinotecano , Camundongos , Microssomos Hepáticos/metabolismo , Inibidores da Topoisomerase I , Transplante HeterólogoRESUMO
[reaction: see text] Both 6'- and 4'-fluoro-glycosylated indolo[2,3-a]carbazoles are substrates for base-induced loss of fluorine as a leaving group from sp3 carbon. In the case of alpha-N-glycosylated substrate 3, loss of fluorine from the 6'-position leads to 3,6-anhydroglucose analogue 1. A novel N12,N13-bridged sugar analogue 2 results from loss of 4'-fluorine from beta-N-glycosylated analogue 4. Both analogues 1 and 2 display topo I inhibitory potencies similar to camptothecin.
Assuntos
Carbazóis/síntese química , Carbono/química , Inibidores Enzimáticos/síntese química , Flúor/química , Glicosídeos/síntese química , Compostos Heterocíclicos de Anel em Ponte/síntese química , Hidrocarbonetos Fluorados/síntese química , Indóis/síntese química , Inibidores da Topoisomerase I , Animais , Carbazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Glicosídeos/farmacologia , Compostos Heterocíclicos de Anel em Ponte/farmacologia , Hidrocarbonetos Fluorados/química , Indóis/química , Leucemia P388 , Conformação Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of paclitaxel analogues possessing a macrocyclic structure between the 7 and 10 positions has been prepared. These compounds possess in vitro activity against a paclitaxel resistant cell line and have in vivo activity comparable to paclitaxel.
Assuntos
Antineoplásicos/síntese química , Paclitaxel/análogos & derivados , Taxoides/síntese química , Taxoides/farmacologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Humanos , Concentração Inibidora 50 , Neoplasias Pulmonares/tratamento farmacológico , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/uso terapêutico , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Relação Estrutura-Atividade , Taxoides/uso terapêutico , Moduladores de TubulinaRESUMO
A series of fluoroindolocarbazoles were studied with respect to their topoisomerase I activity, cytotoxicity, selectivity, and in vivo antitumor activity. Emerging from this series was BMS-251873, a potential clinical candidate possessing a robust pharmacological profile including curative antitumor activity against prostate carcinoma.
Assuntos
Antineoplásicos/síntese química , Carbazóis/síntese química , Glucosídeos/síntese química , Neoplasias da Próstata/tratamento farmacológico , Inibidores da Topoisomerase I , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Glucosídeos/química , Glucosídeos/farmacologia , Masculino , Camundongos , Transplante de Neoplasias , Solubilidade , Relação Estrutura-Atividade , Água , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The evolution of 2, a C-4-methylcarbonate analogue of paclitaxel with minimal oral bioavailability and oral efficacy, into its C-3'-t-butyl-3'-N-t-butyloxycarbonyl analogue (15i), a novel taxane with oral efficacy in preclinical models that is comparable to iv administered paclitaxel, is described.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/farmacocinética , Taxoides/farmacocinética , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Disponibilidade Biológica , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Camundongos , Ratos , Relação Estrutura-Atividade , Taxoides/química , Taxoides/farmacologiaRESUMO
Two novel antitumor alkaloids, Stephacidin A and B, were isolated from the solid fermentation of Aspergillus ochraceus WC76466. Both alkaloids exhibit in vitro cytotoxicity against a number of human tumor cell lines; however, stephacidin B demonstrated more potent and selective antitumor activities, especially against prostate testeosterone-dependent LNCaP cells with IC50 value of 60 nM. The structures of stephacidin A and B were established on the basis of the NMR data and X-ray crystallography. With 15 rings and 9 chiral centers, stephacidin B represents one of the most structurally complex and novel alkaloids occurring in nature.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Aspergillus ochraceus/química , Indóis/química , Indóis/isolamento & purificação , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Antineoplásicos/isolamento & purificação , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos , Indóis/farmacologia , Masculino , Estrutura Molecular , Neoplasias Hormônio-Dependentes/patologia , Ressonância Magnética Nuclear Biomolecular , Neoplasias da Próstata/patologia , Testosterona/fisiologia , Células Tumorais CultivadasRESUMO
A fermentation directed product search for potential anticancer drugs conducted by Bristol-Myers in the 1970s and early 1980s resulted in the identification of a novel indolocarbazole (IC) rebeccamycin (RBM) as a potential drug development candidate. Subsequently, an analog program designed to impart distal site in vivo antitumor activity resulted in the discovery of diethylaminoethyl analog of RBM (DEAE-RBM), which is presently undergoing clinical evaluation as NSC 655649 and BMY-27557. Strong DNA intercalation is the primary mechanism of action of DEAE-RBM resulting in the potent catalytic inhibition of both topoisomerases I and II. Precursor feeding fermentation experiments with fluorine-substituted tryptophans yielded novel fluoroindolocarbazoles (FICs). These FICs were identified as targeting topoisomerase (topo) I in a mechanism-based screen and their action on topo I was confirmed by production of topo I-mediated single-strand breaks in DNA at sites essentially identical to those induced by camptothecin. Topo I dependent cytotoxicity was demonstrated for specific FICs using a P388 and camptothecin-resistant P388/CPT45 pair of cell lines, the latter expresses little or no functional topo I. For example, topo I selectivity was greatest with 3,9-difluoro substituted FIC and was least significant and least cytotoxic with 4,8-difluoro substituted FIC. The review focuses on the discovery of the rebeccamycin class of compounds and their structure-activity relationships leading to the development of the clinical candidate BMY-27557 (NSC 655649), as well as the lead identification of the fluoroindolocarbazole class of compounds.