RESUMO
An NMR fragment screen for binders to the bromodomains of BRD4 identified 2-methyl-3-ketopyrroles 1 and 2. Elaboration of these fragments guided by structure-based design provided lead molecules with significant activity in a mouse tumor model. Further modifications to the methylpyrrole core provided compounds with improved properties and enhanced activity in a mouse model of multiple myeloma.
Assuntos
Antineoplásicos/química , Proteínas Nucleares/antagonistas & inibidores , Pirróis/química , Fatores de Transcrição/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Desenho de Fármacos , Meia-Vida , Humanos , Camundongos , Simulação de Dinâmica Molecular , Mieloma Múltiplo/tratamento farmacológico , Proteínas Nucleares/metabolismo , Pirróis/síntese química , Pirróis/farmacocinética , Pirróis/uso terapêutico , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo , Transplante HeterólogoRESUMO
This study describes the synthesis and characterization of five conjugates of poly(ethylene glycol) modified polyethylenimine (PEG-PEIs) coupled in two different synthesis routes to a nonpeptidic pentacyclic RDG-mimetic for integrin receptor-targeted gene delivery. Synthesis of this panel of different conjugates allowed for systematic analysis of structure-activity relationships. Conjugates were therefore characterized regarding molecular composition, DNA condensation, size, and zeta potential of self-assembled polyplexes. In vitro characterization included investigation of blood compatibility, binding affinity to receptor-positive and receptor-negative cells measured by flow cytometry, cellular uptake quantified by scintillation counting, and efficiency and specificity of transfection assayed by reporter gene expression. In a first synthetic approach, low molecular weight PEI (LMW-PEI) was PEGylated using a heterobifunctional PEG linker and coupling of the RGD-mimetic was achieved at the distal end of PEG chains. In a second synthesis route, the RGD-mimetic was directly coupled to AB-block-copolymers of PEI (25 kDa) and PEG (30 kDa). Interactions of RGD-PEG-LMW-PEI conjugates with DNA were strongly impaired, whereas PEG-PEI-RGD conjugates were more promising candidates due to their physicochemical properties and higher receptor specificity. The binding, uptake, and transfection efficiency in receptor-positive cells was strongly increased upon conjugation of the RGD-mimetic to AB-block-copolymers of PEG-PEI and depended on the degree of peptide substitution. The conjugates of PEG-PEI AB-block-copolymers with low ligand density of the RGD-mimetic appear to be promising candidates for in vivo cancer gene therapy.
Assuntos
Materiais Biomiméticos/química , Materiais Biomiméticos/metabolismo , Técnicas de Transferência de Genes , Integrina alfaVbeta3/metabolismo , Oligopeptídeos/química , Polietilenoglicóis/química , Polietilenoimina/química , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/metabolismo , Materiais Biomiméticos/síntese química , Linhagem Celular Tumoral , DNA/metabolismo , Regulação da Expressão Gênica , Humanos , Ligantes , Maleimidas/química , Propionatos/química , Compostos de Sulfidrila/química , TransfecçãoRESUMO
Matrix metalloproteinases (MMPs) have been implicated in several pathologies. At Abbott Laboratories, the matrix metalloproteinases inhibitor drug discovery program has focused on the discovery of a potent, selective, orally bioavailable MMP inhibitor for the treatment of cancer. The program evolved from early succinate-based inhibitors to utilizing in-house technology such as SAR by NMR to develop a novel class of biaryl hydroxamate MMP inhibitors. The metabolic instability of the biaryl hydroxamates led to the discovery of a new class of N-formylhydroxylamine (retrohydroxamate) biaryl ethers, exemplified by ABT-770 (16). Toxicity issues with this pre-clinical candidate led to the discovery of another novel class of retrohydroxamate MMP inhibitors, the phenoxyphenyl sulfones such as ABT-518 (19j). ABT-518 is a potent, orally bioavailable, selective inhibitor of MMP-2 and 9 over MMP-1 that has been evaluated in Phase I clinical trials in cancer patients.
Assuntos
Indústria Farmacêutica , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Animais , Desenho de Fármacos , Humanos , Espectroscopia de Ressonância Magnética , Relação Estrutura-AtividadeRESUMO
A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.
Assuntos
Antineoplásicos/síntese química , Formamidas/síntese química , Hidroxilaminas/síntese química , Metaloendopeptidases/antagonistas & inibidores , Inibidores de Proteases/síntese química , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular , Formamidas/química , Formamidas/farmacocinética , Formamidas/farmacologia , Hidroxilaminas/química , Hidroxilaminas/farmacocinética , Hidroxilaminas/farmacologia , Macaca fascicularis , Inibidores de Metaloproteinases de Matriz , Camundongos , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Trifluoromethyl ketones were found to be inhibitors of histone deacetylases (HDACs). Optimization of this series led to the identification of submicromolar inhibitors such as 20 that demonstrated antiproliferative effects against the HT1080 and MDA 435 cell lines.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Cetonas/química , Cetonas/farmacologia , Acetilação , Western Blotting , Neoplasias da Mama/metabolismo , Ciclo Celular/efeitos dos fármacos , Fibrossarcoma/metabolismo , Histonas/metabolismo , Humanos , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacologia , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Alpha-keto ester and amides were found to be potent inhibitors of histone deacetylase. Nanomolar inhibitors against the isolated enzyme and sub-micromolar inhibitors of cellular proliferation were obtained. The alpha-keto amide 30 also exhibited significant anti-tumor effects in an in vivo tumor model.
Assuntos
Amidas/química , Amidas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Animais , Linhagem Celular Tumoral , Histona Desacetilases/metabolismo , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Several heterocyclic ketones were investigated as potential inhibitors of histone deacetylase. Nanomolar inhibitors such as 22 and 25 were obtained, the anti-proliferative activity of which were shown to be mediated by HDAC inhibition.