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1.
ACS Med Chem Lett ; 9(11): 1117-1122, 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30429955

RESUMO

The multifunctional cytokine TGFß plays a central role in regulating antitumor immunity. It has been postulated that inhibition of TGFß signaling in concert with checkpoint blockade will provide improved and durable immune response against tumors. Herein, we describe a novel series of 4-azaindole TGFß receptor kinase inhibitors with excellent selectivity for TGFß receptor 1 kinase. The combination of compound 3f and an antimouse-PD-1 antibody demonstrated significantly improved antitumor efficacy compared to either treatment alone in a murine tumor model.

2.
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
3.
Bioorg Med Chem Lett ; 27(23): 5267-5271, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29102228

RESUMO

Macrocyclic pyrrolobenzodiazepine dimers were designed and evaluated for use as antibody-drug conjugate payloads. Initial structure-activity exploration established that macrocyclization could increase the potency of PBD dimers compared with non-macrocyclic analogs. Further optimization overcame activity-limiting solubility issues, leading to compounds with highly potent (picomolar) activity against several cancer cell lines. High levels of in vitro potency and specificity were demonstrated with an anti-mesothelin conjugate.


Assuntos
Anticorpos/metabolismo , Antineoplásicos/farmacologia , Benzodiazepinas/farmacologia , Compostos Macrocíclicos/farmacologia , Pirróis/farmacologia , Anticorpos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Benzodiazepinas/síntese química , Benzodiazepinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dimerização , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Solubilidade , Relação Estrutura-Atividade
4.
Eur J Pharmacol ; 812: 104-112, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28690193

RESUMO

Alzheimer's disease is associated with the accumulation of amyloid-ß (Aß) in the brain. In particular, the 42-amino acid form, Aß1-42, is thought to play a key role in the disease. It is therefore of interest that diverse compounds, known as γ-secretase modulators (GSM), can selectively decrease Aß1-42 production without inhibiting the production of other forms of Aß. Here we describe the novel discovery of synergistic inhibition of Aß by certain combinations of GSMs. Cell cultures were treated with pairwise combinations of GSMs to determine how Aß peptide production was affected. Analysis of isobolograms and calculation of the combination index showed that BMS-869780 and GSM-2 were highly synergistic. Additional combinations of GSMs revealed that inhibition of Aß occurred only when one GSM was of the "acid GSM" structural class and the other was of the "non-acid GSM" class. A total of 15 representative acid/non-acid GSM combinations were shown to inhibit Aß production, whereas 10 pairwise combinations containing two acid GSMs or containing two non-acid GSMs did not inhibit Aß. We also discovered that lasalocid, a natural product, is a potent GSM. Lasalocid is unique in that it did not synergize with other GSMs. Synergism did not translate in vivo perhaps because of biochemical differences between the cell culture model and brain. These findings reinforce the pharmacological differences between different structural classes of GSMs, and may help to exploit the potential of γ-secretase as a drug target.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/biossíntese , Fragmentos de Peptídeos/biossíntese , Inibidores de Proteases/farmacologia , Acetatos/farmacologia , Animais , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Camundongos , Piperidinas/farmacologia
7.
ACS Med Chem Lett ; 7(1): 40-5, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26819663

RESUMO

Efforts to identify a potent, reversible, nonsteroidal CYP17A1 lyase inhibitor with good selectivity over CYP17A1 hydroxylase and CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate cancer (CRPC) culminated in the discovery of BMS-351 (compound 18), a pyridyl biaryl benzimidazole with an excellent in vivo profile. Biological evaluation of BMS-351 at a dose of 1.5 mg in castrated cynomolgus monkeys revealed a remarkable reduction in testosterone levels with minimal glucocorticoid and mineralcorticoid perturbation. Based on a favorable profile, BMS-351 was selected as a candidate for further preclinical evaluation.

8.
ACS Med Chem Lett ; 6(8): 908-12, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26288692

RESUMO

BMS-641988 (23) is a novel, nonsteroidal androgen receptor antagonist designed for the treatment of prostate cancer. The compound has high binding affinity for the AR and acts as a functional antagonist in vitro. BMS-641988 is efficacious in multiple human prostate cancer xenograft models, including CWR22-BMSLD1 where it displays superior efficacy relative to bicalutamide. Based on its promising preclinical profile, BMS-641988 was selected for clinical development.

9.
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 , Proteínas Reguladoras de Apoptose , 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
10.
ACS Med Chem Lett ; 6(7): 770-5, 2015 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-26191364

RESUMO

A series of dimeric macrocyclic compounds were prepared and evaluated as antagonists for inhibitor of apoptosis proteins. The most potent analogue 11, which binds to XIAP and c-IAP proteins with high affinity and induces caspase-3 activation and ultimately cell apoptosis, inhibits growth of human melanoma and colorectal cell lines at low nanomolar concentrations. Furthermore, compound 11 demonstrated significant antitumor activity in the A875 human melanoma xenograft model at doses as low as 2 mg/kg on a q3d schedule.

11.
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.

12.
Bioorg Med Chem Lett ; 25(9): 1905-9, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25857941
13.
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
14.
Drug Discov Today ; 19(7): 869-81, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24239727

RESUMO

Antibody-drug conjugates (ADCs) aim to take advantage of the specificity of monoclonal antibodies (mAbs) to deliver potent cytotoxic drugs selectively to antigen-expressing tumor cells. Despite the simple concept, various parameters must be considered when designing optimal ADCs, such as selection of the appropriate antigen target and conjugation method. Each component of the ADC (the antibody, linker and drug) must also be optimized to fully realize the goal of a targeted therapy with improved efficacy and tolerability. Advancements over the past several decades have led to a new generation of ADCs comprising non-immunogenic mAbs, linkers with balanced stability and highly potent cytotoxic agents. Although challenges remain, recent clinical success has generated intense interest in this therapeutic class.


Assuntos
Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/imunologia , Antineoplásicos/imunologia , Previsões , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia
15.
J Neurosci ; 32(21): 7137-45, 2012 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-22623658

RESUMO

Tau is a microtubule (MT)-stabilizing protein that is altered in Alzheimer's disease (AD) and other tauopathies. It is hypothesized that the hyperphosphorylated, conformationally altered, and multimeric forms of tau lead to a disruption of MT stability; however, direct evidence is lacking in vivo. In this study, an in vivo stable isotope-mass spectrometric technique was used to measure the turnover, or dynamicity, of MTs in brains of living animals. We demonstrated an age-dependent increase in MT dynamics in two different tau transgenic mouse models, 3xTg and rTg4510. MT hyperdynamicity was dependent on tau expression, since a reduction of transgene expression with doxycycline reversed the MT changes. Treatment of rTg4510 mice with the epothilone, BMS-241027, also restored MT dynamics to baseline levels. In addition, MT stabilization with BMS-241027 had beneficial effects on Morris water maze deficits, tau pathology, and neurodegeneration. Interestingly, pathological and functional benefits of BMS-241027 were observed at doses that only partially reversed MT hyperdynamicity. Together, these data suggest that tau-mediated loss of MT stability may contribute to disease progression and that very low doses of BMS-241027 may be useful in the treatment of AD and other tauopathies.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Epotilonas/uso terapêutico , Microtúbulos/patologia , Degeneração Neural/tratamento farmacológico , Tauopatias/tratamento farmacológico , Moduladores de Tubulina/uso terapêutico , Proteínas tau/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Transtornos Cognitivos/complicações , Transtornos Cognitivos/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Doxiciclina/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/psicologia , Epotilonas/farmacologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microtúbulos/efeitos dos fármacos , Tauopatias/complicações , Tauopatias/genética , Tauopatias/patologia , Tauopatias/psicologia , Moduladores de Tubulina/farmacologia , Proteínas tau/antagonistas & inibidores , Proteínas tau/biossíntese , Proteínas tau/genética
16.
Org Lett ; 14(1): 214-7, 2012 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-22148911

RESUMO

In the presence of AlMe(3), amines can be directly coupled with acids through dimethylaluminum amide intermediates to form the corresponding amides. A wide range of amines and acids including less nucleophilic amines, bulky amines, unprotected secondary amino acids, and acids with poor solubility were coupled smoothly to give the desired products in 55-98% yields.


Assuntos
Ácidos/química , Alumínio/química , Amidas/síntese química , Aminas/química , Compostos Organometálicos/química , Estrutura Molecular
17.
Bioorg Med Chem Lett ; 21(2): 781-5, 2011 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-21177105
18.
Bioorg Med Chem Lett ; 20(15): 4578-81, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20594844

RESUMO

Efficient regioselective syntheses of conjugates of folic acid and cytotoxic agents derived from natural epothilones are described. These folate receptor (FR) targeting compounds are water soluble and incorporate a hydrophilic peptide-based spacer unit and a reducible self-immolative disulfide-based linker system between the FR-targeting ligand and the parent drug.


Assuntos
Antineoplásicos/síntese química , Epotilonas/química , Receptores de Folato com Âncoras de GPI/antagonistas & inibidores , Ácido Fólico/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Dissulfetos/química , Epotilonas/síntese química , Epotilonas/farmacologia , Receptores de Folato com Âncoras de GPI/metabolismo , Ácido Fólico/síntese química , Ácido Fólico/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
19.
J Med Chem ; 52(21): 6527-30, 2009 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-19821562

RESUMO

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/farmacologia
20.
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.

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