RESUMO
The design of potent Pin1 inhibitors has been challenging because its active site specifically recognizes a phospho-protein epitope. The de novo design of phosphate-based Pin1 inhibitors focusing on the phosphate recognition pocket and the successful replacement of the phosphate group with a carboxylate have been previously reported. The potency of the carboxylate series is now further improved through structure-based optimization of ligand-protein interactions in the proline binding site which exploits the H-bond interactions necessary for Pin1 catalytic function. Further optimization using a focused library approach led to the discovery of low nanomolar non-phosphate small molecular Pin1 inhibitors. Structural modifications designed to improve cell permeability resulted in Pin1 inhibitors with low micromolar anti-proliferative activities against cancer cells.
Assuntos
Benzimidazóis/farmacologia , Ácidos Carboxílicos/farmacologia , Inibidores Enzimáticos/farmacologia , Peptidilprolil Isomerase/antagonistas & inibidores , Fosfatos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Domínio Catalítico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Peptidilprolil Isomerase de Interação com NIMA , Peptidilprolil Isomerase/metabolismo , Relação Estrutura-AtividadeRESUMO
The M2 isoform of pyruvate kinase is an emerging target for antitumor therapy. In this letter, we describe the discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as potent and selective PKM2 activators which were found to have a novel binding mode. The original lead identified from high throughput screening was optimized into an efficient series via computer-aided structure-based drug design. Both a representative compound from this series and an activator described in the literature were used as molecular tools to probe the biological effects of PKM2 activation on cancer cells. Our results suggested that PKM2 activation alone is not sufficient to alter cancer cell metabolism.
Assuntos
Benzimidazóis/química , Proteínas de Transporte/agonistas , Proteínas de Membrana/agonistas , Pirimidinonas/química , Hormônios Tireóideos/agonistas , Sítios de Ligação , Proteínas de Transporte/metabolismo , Linhagem Celular , Desenho Assistido por Computador , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Cinética , Proteínas de Membrana/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Pirimidinonas/síntese química , Pirimidinonas/metabolismo , Relação Estrutura-Atividade , Hormônios Tireóideos/metabolismo , Proteínas de Ligação a Hormônio da TireoideRESUMO
(S)-1-((4-(3-(6-Amino-5-methoxypyridin-3-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-ol, 1, was recently identified as a potent inhibitor of the oncogenic kinase bRAF. Compounds containing 3-methoxy-2-aminopyridine, as in 1, comprised a promising lead series because of their high ligand efficiency and excellent ADME profile. However, following metabolic oxidation, compounds in this series also demonstrated two significant safety risks: mutagenic potential and time-dependent drug-drug interaction (TDI). Metabolite identification studies revealed formation of a reactive metabolite. We hypothesized that minimizing or blocking the formation of such a metabolite would mitigate the safety liabilities. Our investigation demonstrated that structural modifications which either reduced the electron density of the 3-methoxy-2-aminopyridine ring or blocked the reactive site following metabolic oxidation were successful in reducing TDI and AMES mutagenicity.
Assuntos
Aminopiridinas/química , Aminopiridinas/metabolismo , Elétrons , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Testes de Mutagenicidade , Oxirredução , Fatores de TempoRESUMO
The P21-activated kinases (PAK) are emerging antitumor therapeutic targets. In this paper, we describe the discovery of potent PAK inhibitors guided by structure-based drug design. In addition, the efflux of the pyrrolopyrazole series was effectively reduced by applying multiple medicinal chemistry strategies, leading to a series of PAK inhibitors that are orally active in inhibiting tumor growth in vivo.
Assuntos
Antineoplásicos/síntese química , Pirazóis/síntese química , Pirróis/síntese química , Quinases Ativadas por p21/antagonistas & inibidores , Administração Oral , Amidas/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Carbamatos/química , Carbamatos/farmacocinética , Carbamatos/farmacologia , Cristalografia por Raios X , Cães , Humanos , Ligação de Hidrogênio , Camundongos , Modelos Moleculares , Conformação Molecular , Permeabilidade , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Oxobenzimidazoles (e.g., 1), a novel series of androgen receptor (AR) antagonists, were discovered through de novo design guided by structure-based drug design. The compounds in this series were reasonably permeable and metabolically stable, but suffered from poor solubility. The incorporation of three dimensional structural features led to improved solubility. In addition, the observation of a 'flipped' binding mode of an oxobenzimidazole analog in an AR ligand binding domain (LBD) model, led to the design and discovery of the novel oxindole series (e.g., 2) that is a potent full antagonist of AR.
Assuntos
Antagonistas de Receptores de Andrógenos/síntese química , Antineoplásicos/síntese química , Benzimidazóis/síntese química , Indóis/síntese química , Receptores Androgênicos/química , Antagonistas de Receptores de Andrógenos/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Descoberta de Drogas , Humanos , Indóis/farmacologia , Ligantes , Masculino , Modelos Moleculares , Neoplasias da Próstata , Ligação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptores Androgênicos/metabolismo , Solubilidade , Relação Estrutura-AtividadeRESUMO
High throughput cell-based screening led to the identification of 3-aryloxy lactams as potent androgen receptor (AR) antagonists. Refinement of these leads to improve the ADME profile and remove residual agonism led to the discovery of 12, a potent full antagonist with greater oral bioavailability. Improvements in the ADME profile were realized by designing more ligand-efficient molecules with reduced molecular weights and lower lipophilicities.
Assuntos
Descoberta de Drogas , Lactamas/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/química , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , Humanos , Lactamas/síntese química , Lactamas/química , Masculino , Modelos Moleculares , Estrutura Molecular , Neoplasias da Próstata/cirurgia , Receptores Androgênicos/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
An aryloxy tetramethylcyclobutane was identified as a novel template for androgen receptor (AR) antagonists via cell-based high-throughput screening. Follow-up to the initial "hit" established 5 as a viable lead. Further optimization to achieve full AR antagonism led to the discovery of 26 and 30, both of which demonstrated excellent in vivo tumor growth inhibition upon oral administration in a castration-resistant prostate cancer (CRPC) animal model.
Assuntos
Antagonistas de Androgênios/síntese química , Antineoplásicos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Ciclobutanos/síntese química , Pirazóis/síntese química , Administração Oral , Antagonistas de Androgênios/farmacocinética , Antagonistas de Androgênios/farmacologia , Androgênios/síntese química , Androgênios/farmacocinética , Androgênios/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular , Ciclobutanos/farmacocinética , Ciclobutanos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Ensaios de Triagem em Larga Escala , Humanos , Ligantes , Masculino , Camundongos , Camundongos Nus , Modelos Moleculares , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Pirazóis/farmacocinética , Pirazóis/farmacologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
N-{trans-3-[(5-Cyano-6-methylpyridin-2-yl)oxy]-2,2,4,4-tetramethylcyclobutyl}imidazo[1,2-a]pyrimidine-3-carboxamide (1) was recently identified as a full antagonist of the androgen receptor, demonstrating excellent in vivo tumor growth inhibition in castration-resistant prostate cancer (CRPC). However, the imidazo[1,2-a]pyrimidine moiety is rapidly metabolized by aldehyde oxidase (AO). The present paper describes a number of medicinal chemistry strategies taken to avoid the AO-mediated oxidation of this particular system. Guided by an AO protein structure-based model, our investigation revealed the most probable site of AO oxidation and the observation that altering the heterocycle or blocking the reactive site are two of the more effective strategies for reducing AO metabolism. These strategies may be useful for other drug discovery programs.
Assuntos
Aldeído Oxidase/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Ciclobutanos/química , Imidazóis/química , Pirimidinas/química , Aldeído Oxidase/metabolismo , Domínio Catalítico , Humanos , Imidazóis/síntese química , Imidazóis/metabolismo , Modelos Moleculares , Oxirredução , Ligação Proteica , Pirimidinas/síntese química , Pirimidinas/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Despite abundant evidence that aberrant Rho-family GTPase activation contributes to most steps of cancer initiation and progression, there is a dearth of inhibitors of their effectors (e.g., p21-activated kinases). Through high-throughput screening and structure-based design, we identify PF-3758309, a potent (K(d) = 2.7 nM), ATP-competitive, pyrrolopyrazole inhibitor of PAK4. In cells, PF-3758309 inhibits phosphorylation of the PAK4 substrate GEF-H1 (IC(50) = 1.3 nM) and anchorage-independent growth of a panel of tumor cell lines (IC(50) = 4.7 +/- 3 nM). The molecular underpinnings of PF-3758309 biological effects were characterized using an integration of traditional and emerging technologies. Crystallographic characterization of the PF-3758309/PAK4 complex defined determinants of potency and kinase selectivity. Global high-content cellular analysis confirms that PF-3758309 modulates known PAK4-dependent signaling nodes and identifies unexpected links to additional pathways (e.g., p53). In tumor models, PF-3758309 inhibits PAK4-dependent pathways in proteomic studies and regulates functional activities related to cell proliferation and survival. PF-3758309 blocks the growth of multiple human tumor xenografts, with a plasma EC(50) value of 0.4 nM in the most sensitive model. This study defines PAK4-related pathways, provides additional support for PAK4 as a therapeutic target with a unique combination of functions (apoptotic, cytoskeletal, cell-cycle), and identifies a potent, orally available small-molecule PAK inhibitor with significant promise for the treatment of human cancers.
Assuntos
Proliferação de Células/efeitos dos fármacos , Modelos Moleculares , Neoplasias/metabolismo , Pirazóis/farmacologia , Pirróis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Quinases Ativadas por p21/antagonistas & inibidores , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Pirazóis/química , Pirazóis/metabolismo , Pirróis/química , Pirróis/metabolismo , Fatores de Troca de Nucleotídeo Guanina RhoRESUMO
Following the discovery of a novel series of phosphate-containing small molecular Pin1 inhibitors, the drug design strategy shifted to replacement of the phosphate group with an isostere with potential better pharmaceutical properties. The initial loss in potency of carboxylate analogs was likely due to weaker charge-charge interactions in the putative phosphate binding pocket and was subsequently recovered by structure-based optimization of ligand-protein interactions in the proline binding site, leading to the discovery of a sub-micromolar non-phosphate small molecular Pin1 inhibitor.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Peptidilprolil Isomerase/antagonistas & inibidores , Peptidilprolil Isomerase/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Modelos Moleculares , Peptidilprolil Isomerase de Interação com NIMA , Peptidilprolil Isomerase/química , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Pin1 is a member of the cis-trans peptidyl-prolyl isomerase family with potential anti-cancer therapeutic value. Here we report structure-based de novo design and optimization of novel Pin1 inhibitors. Without a viable lead from internal screenings, we designed a series of novel Pin1 inhibitors by interrogating and exploring a protein crystal structure of Pin1. The ligand efficiency of the initial concept molecule was optimized with integrated SBDD and parallel chemistry approaches, resulting in a more attractive lead series.
Assuntos
Inibidores Enzimáticos/química , Peptidilprolil Isomerase/antagonistas & inibidores , Sequência de Aminoácidos , Sítios de Ligação , Técnicas de Química Combinatória , Simulação por Computador , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Peptidilprolil Isomerase de Interação com NIMA , Peptidilprolil Isomerase/metabolismo , Relação Estrutura-AtividadeRESUMO
Since the discovery that FK-506 promotes neurite outgrowth, considerable attention has been focused on the development of potent nonimmunosuppressive ligands for FK-506 binding proteins (FKBPs). Such neuroimmunophilin agents have been reported to show neuroregenerative activity in a variety of cell and animal models including neurite outgrowth, age-related cognitive decline, Parkinson's disease, peripheral nerve injury, optic nerve degeneration, and diabetic neuropathy. We have designed and synthesized a unique series of tetracyclic aza-amides that have been shown to be potent FKBP12 rotamase inhibitors. The structure-activity relationships established in this study have demonstrated diverse structural modifications that result in potent rotamase inhibitory activity.
Assuntos
Amidas/síntese química , Compostos Aza/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Fármacos Neuroprotetores/síntese química , Proteína 1A de Ligação a Tacrolimo/antagonistas & inibidores , Proteína 1A de Ligação a Tacrolimo/química , Amidas/química , Compostos Aza/química , Sítios de Ligação , Compostos Heterocíclicos de 4 ou mais Anéis/química , Ligação de Hidrogênio , Isoquinolinas/síntese química , Isoquinolinas/química , Ligantes , Fármacos Neuroprotetores/química , Relação Estrutura-Atividade , Tacrolimo/químicaRESUMO
[reaction: see text] Treatment of 1,4-dilithio-1,3-butadiyne (1) with dichalcogenides RSSR or RSeSeR affords dithio- and diseleno-1,3-butadiynes (2, 3), perthio- and perseleno-[3]-cumulenes (4, 5), perthio- and perseleno-1,3-butadienes (6, 7), and/or perthio- and perseleno-but-1-ene-3-ynes (8, 9). The products can be controlled by stoichiometry and temperature, by the presence or absence of oxygen, and by choice of the "R" group. By X-ray crystallography, hexa(methylthio)-1,3-butadiene is highly twisted, with a torsion angle [Phi(CCCC)] of 84.7 degrees and an elongated C(2)-C(3) distance of 1.484(3) A.