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1.
J Med Chem ; 58(6): 2855-61, 2015 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-25695766

RESUMO

Affinity selection screening of macrocycle libraries derived from DNA-programmed chemistry identified XIAP BIR2 and BIR3 domain inhibitors that displace bound pro-apoptotic caspases. X-ray cocrystal structures of key compounds with XIAP BIR2 suggested potency-enhancing structural modifications. Optimization of dimeric macrocycles with similar affinity for both domains were potent pro-apoptotic agents in cancer cell lines and efficacious in shrinking tumors in a mouse xenograft model.


Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Compostos Macrocíclicos/química , Compostos Macrocíclicos/uso terapêutico , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Mama/efeitos dos fármacos , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Cristalografia por Raios X , Descoberta de Drogas , Feminino , Biblioteca Gênica , Humanos , Compostos Macrocíclicos/farmacocinética , Camundongos , Modelos Moleculares , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
2.
J Med Chem ; 58(3): 1556-62, 2015 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-25584393

RESUMO

The prominent role of IAPs in controlling cell death and their overexpression in a variety of cancers has prompted the development of IAP antagonists as potential antitumor therapies. We describe the identification of a series of heterodimeric antagonists with highly potent antiproliferative activities in cIAP- and XIAP-dependent cell lines. Compounds 15 and 17 further demonstrate curative efficacy in human melanoma and lung cancer xenograft models and are promising candidates for advanced studies.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Neoplasias Experimentais/tratamento farmacológico , Prolina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Neoplasias Experimentais/patologia , Prolina/síntese química , Prolina/química , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 24(21): 5022-9, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25278234

RESUMO

Bivalent heterodimeric IAP antagonists that incorporate (R)-tetrahydroisoquinoline in the P3' subunit show high affinity for the BIR2 domain and demonstrated potent IAP inhibitory activities in biochemical and cellular assays. Potent in vivo efficacy was observed in a variety of human tumor xenograft models. The bivalent heterodimeric molecule 3 with a P3-P3' benzamide linker induced pharmacodynamic markers of apoptosis and was efficacious when administered intravenously at a dose of 1mg/kg to mice harboring A875 human melanoma tumors. Analog 5, with a polyamine group incorporated at the P2' thiovaline side chain exhibited antiproliferative activity against the P-gp expressing HCT116/VM46 cell line.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Melanoma/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Tetra-Hidroisoquinolinas/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Moleculares , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Drug Metab Dispos ; 40(9): 1677-85, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22627466

RESUMO

Although it is widely accepted that one can extend the pharmacokinetic half-life of a therapeutic protein by covalent conjugation with polyethylene glycol (PEG), the disposition properties of such biologics have not yet been fully evaluated. Therefore, a novel [¹4C]-labeling method was developed that can be applied to a biologic conjugated with PEG through a maleimide-cysteine reaction. The method was used to study the tissue and tumor distribution of a PEGylated Adnectin, a recombinant protein derived from the 10th type III domain of fibronectin, in nude mice bearing human xenograft tumors. The PEGylated Adnectin contained a 40-kDa branched PEG (P40B) that was labeled with [¹4C] at the linker region between the PEG and Adnectin, without compromising cellular activity and plasma half-life in mice. After a single intravenous or intraperitoneal dose (33 mg/kg, 1.7 µCi per mouse) of [¹4C]-P40B-Adnectin, quantitative whole-body autoradiography analysis revealed that the liver had the highest uptake of the radioactivity among nontumor tissues, followed by the kidneys and lung. The muscle and brain showed the least penetration of the radioactivity among all tissues examined. In addition, the [¹4C]-P40B-EI-tandem penetrated into the tumor tissue, although the extent of accumulation was largely dependent on tumor type. Therefore, it was possible to assess the tissue distribution of a PEGylated biologic after it had been [¹4C] labeled using the novel method described herein.


Assuntos
Antineoplásicos/farmacocinética , Produtos Biológicos/farmacocinética , Radioisótopos de Carbono/farmacocinética , Fibronectinas/farmacocinética , Marcação por Isótopo/métodos , Neoplasias/metabolismo , Polietilenoglicóis/farmacocinética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Autorradiografia , Produtos Biológicos/administração & dosagem , Produtos Biológicos/síntese química , Radioisótopos de Carbono/administração & dosagem , Radioisótopos de Carbono/química , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Feminino , Fibronectinas/administração & dosagem , Fibronectinas/síntese química , Fibronectinas/genética , Humanos , Injeções Intraperitoneais , Injeções Intravenosas , Camundongos , Camundongos Nus , Mutação , Neoplasias/patologia , Fosforilação , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/síntese química , Engenharia de Proteínas , Receptor IGF Tipo 1/metabolismo , Proteínas Recombinantes/farmacocinética , Distribuição Tecidual , Carga Tumoral , Imagem Corporal Total
5.
Structure ; 20(2): 259-69, 2012 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-22325775

RESUMO

Adnectins are targeted biologics derived from the tenth type III domain of human fibronectin (¹°Fn3), a member of the immunoglobulin superfamily. Target-specific binders are selected from libraries generated by diversifying the three ¹°Fn3 loops that are analogous to the complementarity determining regions of antibodies. The crystal structures of two Adnectins were determined, each in complex with its therapeutic target, EGFR or IL-23. Both Adnectins bind different epitopes than those bound by known monoclonal antibodies. Molecular modeling suggests that some of these epitopes might not be accessible to antibodies because of the size and concave shape of the antibody combining site. In addition to interactions from the Adnectin diversified loops, residues from the N terminus and/or the ß strands interact with the target proteins in both complexes. Alanine-scanning mutagenesis confirmed the calculated binding energies of these ß strand interactions, indicating that these nonloop residues can expand the available binding footprint.


Assuntos
Receptores ErbB/química , Fibronectinas/química , Interleucina-23/química , Fragmentos de Peptídeos/química , Sequência de Aminoácidos , Substituição de Aminoácidos , Cristalografia por Raios X , Fibronectinas/genética , Humanos , Ligações de Hidrogênio , Modelos Moleculares , Dados de Sequência Molecular , Complexos Multiproteicos/química , Mutagênese Sítio-Dirigida , Fragmentos de Peptídeos/genética , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Quaternária de Proteína , Estrutura Secundária de Proteína , Homologia Estrutural de Proteína , Ressonância de Plasmônio de Superfície , Propriedades de Superfície
6.
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
7.
MAbs ; 3(1): 38-48, 2011 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21099371

RESUMO

Engineered domains of human fibronectin (Adnectins™) were used to generate a bispecific Adnectin targeting epidermal growth factor receptor (EGFR) and insulin-like growth factor-I receptor (IGF-IR), two transmembrane receptors that mediate proliferative and survival cell signaling in cancer. Single-domain Adnectins that specifically bind EGFR or IGF-IR were generated using mRNA display with a library containing as many as 10 ( 13) Adnectin variants. mRNA display was also used to optimize lead Adnectin affinities, resulting in clones that inhibited EGFR phosphorylation at 7 to 38 nM compared to 2.6 µM for the parental clone. Individual, optimized, Adnectins specific for blocking either EGFR or IGF-IR signaling were engineered into a single protein (EI-Tandem Adnectin). The EI-Tandems inhibited phosphorylation of EGFR and IGF-IR, induced receptor degradation, and inhibited down-stream cell signaling and proliferation of human cancer cell lines (A431, H292, BxPC3 and RH41) with IC 50 values ranging from 0.1 to 113 nM. Although Adnectins bound to EGFR at a site distinct from those of anti-EGFR antibodies cetuximab, panitumumab and nimotuzumab, like the antibodies, the anti-EGFR Adnectins blocked the binding of EGF to EGFR. PEGylated EI-Tandem inhibited the growth of both EGFR and IGF-IR driven human tumor xenografts, induced degradation of EGFR, and reduced EGFR phosphorylation in tumors. These results demonstrate efficient engineering of bispecific Adnectins with high potency and desired specificity. The bispecificity may improve biological activity compared to monospecific biologics as tumor growth is driven by multiple growth factors. Our results illustrate a technological advancement for constructing multi-specific biologics in cancer therapy.


Assuntos
Receptores ErbB/antagonistas & inibidores , Fibronectinas/química , Fragmentos de Peptídeos/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Receptores ErbB/metabolismo , Feminino , Humanos , Immunoblotting , Cinética , Camundongos , Camundongos Nus , Dados de Sequência Molecular , Panitumumabe , Fragmentos de Peptídeos/metabolismo , Fosforilação/efeitos dos fármacos , Ligação Proteica , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Pure Appl Chem ; 81(6): 1051-1063, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-20046887

RESUMO

A collaborative multidisciplinary research project is described in which new natural product anticancer drug leads are obtained from a diverse group of organisms, constituted by tropical plants, aquatic cyanobacteria, and filamentous fungi. Information is provided on how these organisms are collected and processed. The types of bioassays are indicated in which crude extracts of these acquisitions are tested. Progress made in the isolation of lead bioactive secondary metabolites from three tropical plants is discussed.

11.
Bioorg Med Chem Lett ; 18(16): 4615-9, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18653333

RESUMO

Members of a novel class of 4-amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones were identified as potent dual ErbB-2/EGFR kinase inhibitors using concept-guided design approach. These compounds inhibited the growth of ErbB-2 over-expressing human tumor cell lines (BT474, N87, and SK-BR-3) in vitro. Compound 15 emerged as a key lead and showed significant ability to inhibit growth factor-induced receptor phosphorylation in SK-BR-3 cells (IC(50)=54 nM) and cellular proliferation in vitro (IC(50)=14, 58, and 58 nM for BT474, N87, and SK-BR-3 respectively). The X-ray co-crystal structure of EGFR with a close analog (17) was determined and validated our design rationale.


Assuntos
Química Farmacêutica/métodos , Receptores ErbB/antagonistas & inibidores , Hidrazonas/química , Hidrazonas/síntese química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/síntese química , Receptor ErbB-2/antagonistas & inibidores , Animais , Desenho de Drogas , Humanos , Hidrazonas/farmacologia , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Oximas/química , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
12.
Bioorg Med Chem Lett ; 18(12): 3495-9, 2008 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-18508264

RESUMO

We herein disclose a novel series of 4-aminopyrimidine-5-carbaldehyde oximes that are potent and selective inhibitors of both EGFR and ErbB-2 tyrosine kinases, with IC(50) values in the nanomolar range. Structure-activity relationship (SAR) studies elucidated a critical role for the 4-amino and C-6 arylamino moieties. The X-ray co-crystal structure of EGFR with 37 was determined and validated our design rationale.


Assuntos
Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Oximas/farmacologia , Pirimidinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligações de Hidrogênio , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Oximas/síntese química , Oximas/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade
13.
Mol Pharmacol ; 73(2): 338-48, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17975007

RESUMO

JNJ-28871063 is a potent and highly selective pan-ErbB kinase inhibitor from a novel aminopyrimidine oxime structural class that blocks the proliferation of epidermal growth factor receptor (EGFR; ErbB1)- and ErbB2-overexpressing cells but does not affect the growth of non-ErbB-overexpressing cells. Treatment of human cancer cells with JNJ-28871063 inhibited phosphorylation of functionally important tyrosine residues in both EGFR and ErbB2 and blocked downstream signal transduction pathways responsible for proliferation and survival. A single dose of compound reduced phosphorylation of ErbB2 receptors in tumor-bearing mice, demonstrating target suppression in vivo. Tissue distribution studies show that JNJ-28871063 crosses the blood-brain barrier and penetrates into tumors, where it is able to accumulate to higher levels than those found in the plasma. JNJ-28871063 showed oral antitumor activity in human tumor xenograft models that overexpress EGFR and ErbB2. In an intracranial ErbB2-overexpressing tumor model, JNJ-28871063 extended survival relative to untreated animals. The brain is a primary site of metastasis for EGFR-overexpressing lung cancers and ErbB2-overexpressing breast cancers. Therefore, the ability to penetrate into the brain could be an advantage over existing therapies such as trastuzumab (Herceptin) and cetuximab (Erbitux), which are antibodies and do not cross the blood-brain barrier. These results show that JNJ-28871063 is orally bioavailable, has activity against EGFR and ErbB2-dependent tumor xenografts, and can penetrate into the brain and inhibit ErbB2-overexpressing tumor growth.


Assuntos
Antineoplásicos/uso terapêutico , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Morfolinas/química , Morfolinas/uso terapêutico , Pirimidinas/química , Pirimidinas/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Barreira Hematoencefálica/enzimologia , Neoplasias Encefálicas/enzimologia , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Camundongos , Camundongos Nus , Camundongos SCID , Morfolinas/farmacologia , Pirimidinas/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Receptores Proteína Tirosina Quinases/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
14.
Bioorg Med Chem Lett ; 17(16): 4557-61, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17574416

RESUMO

Two series of 3,4-disubstituted pyrazole analogues, 3-(benzimidazol-2-yl)-4-[2-(pyridin-3-yl)-vinyl]-pyrazoles (2) and 3-(imidazol-2-yl)-4-[2-(pyridin-3-yl)-vinyl]-pyrazoles (3), were synthesized as novel cyclin-dependent kinase (CDK) inhibitors. Representative compounds showed potent and selective CDK inhibitory activities and inhibited in vitro cellular proliferation in various human tumor cells. The design, synthesis, and preliminary biological evaluation of these pyrazole compounds are reported.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Pirazóis/síntese química , Pirazóis/farmacologia , Linhagem Celular Tumoral , Desenho de Drogas , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
16.
Bioorg Med Chem Lett ; 17(15): 4297-302, 2007 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-17532631

RESUMO

A series of 3,5-disubstituted pyrazolo[3,4-b]pyridine cyclin-dependent kinase (CDK) inhibitors was synthesized. These compounds showed potent and selective CDK inhibitory activities and inhibited in vitro cellular proliferation in cultured human tumor cells. Selected compounds were evaluated in an in vivo tumor xenograft model. The synthesis and biological evaluation of these pyrazolo[3,4-b]pyridines and related compounds are reported.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proteína Quinase CDC2/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Antineoplásicos/química , Células Cultivadas , Humanos , Inibidores de Proteínas Quinases/química , Pirazóis/química , Piridinas/química
18.
Bioorg Med Chem Lett ; 17(5): 1243-5, 2007 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-17234412

RESUMO

The novel compound 3-(1H-benzimidazol-2-yl)-5-isoquinolin-4-ylpyrazolo[1,2-b]pyridine was discovered to be a potent CDK1 inhibitor. Described here is the chemistry for its synthesis, including Pd(II) catalyzed Stille coupling reaction and sulfur(0) induced benzimidazole formation. Its effects on VEGFR-2 kinase activity and tumour cell proliferation are also described.


Assuntos
Proteína Quinase CDC2/antagonistas & inibidores , Piridinas/síntese química , Piridinas/farmacologia , Benzimidazóis , Catálise , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Paládio , Relação Estrutura-Atividade , Enxofre , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/efeitos dos fármacos
19.
Mol Cancer Ther ; 5(10): 2459-67, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17041089

RESUMO

Cell cycle kinase inhibitors have advanced into clinical trials in oncology. One such molecule, JNJ-7706621, is a broad-spectrum inhibitor of the cyclin-dependent kinases and Aurora kinases that mediate G(2)-M arrest and inhibits tumor growth in xenograft models. To determine the putative mechanisms of resistance to JNJ-7706621 that might be encountered in the clinic, the human epithelial cervical carcinoma cell line (HeLa) was exposed to incrementally increasing concentrations of JNJ-7706621. The resulting resistant cell population, designated HeLa-6621, was 16-fold resistant to JNJ-7706621, cross-resistant to mitoxantrone (15-fold) and topotecan (6-fold), and exhibited reduced intracellular drug accumulation of JNJ-7706621. ABCG2 was highly overexpressed at both the mRNA ( approximately 163-fold) and protein levels. The functional role of ABCG2 in mediating resistance to JNJ-7706621 was consistent with the following findings: (a) an ABCG2 inhibitor, fumitremorgin C, restored the sensitivity of HeLa-6621 cells to JNJ-7706621 and to mitoxantrone; (b) human embryonic kidney-293 cells transfected with ABCG2 were resistant to both JNJ-7706621 and mitoxantrone; and (c) resistant cells that were removed from the drug for 12 weeks and reverted to susceptibility to JNJ-7706621 showed near-normal ABCG2 RNA levels. ABCG2 is likely to limit the bioavailability of JNJ-7706621 because oral administration of JNJ-7706621 to Bcrp (the murine homologue of ABCG2) knockout mice resulted in an increase in the plasma concentration of JNJ-7706621 compared with wild-type mice. These findings indicate that ABCG2 mediates the resistance to JNJ-7706621 and alters the absorption of the compound following administration.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/fisiologia , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/farmacologia , Proteínas de Neoplasias/fisiologia , Triazóis/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/biossíntese , Administração Oral , Animais , Antineoplásicos/farmacocinética , Aurora Quinases , Disponibilidade Biológica , Quinases Ciclina-Dependentes/antagonistas & inibidores , Células HeLa , Humanos , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/biossíntese , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Triazóis/farmacocinética
20.
Bioorg Med Chem Lett ; 16(23): 6063-6, 2006 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16979339

RESUMO

A novel 4-aminopyrimidine-5-carboxaldehyde oxime scaffold with inhibitory activity against VEGFR-2 kinase has been identified. With a 4-fluoro-2-methylindol-5-yloxy group at the 6-position and alkyl groups as the oxime side chains, many analogues showed good potency for VEGFR-2. This series also exhibited antiproliferative activity against cancer cells, causing cell accumulation at the G2/M phase of the cell cycle and preventing cells from entering mitosis. Described here are the chemistry, structure-activity relationships (SAR), and biological testing for this series.


Assuntos
Oximas/química , Oximas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Células HeLa , Humanos , Estrutura Molecular , Oximas/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
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