RESUMO
Viruses use a limited set of host pathways for infection. These pathways represent bona fide antiviral targets with low likelihood of viral resistance. We identified the salicylanilide niclosamide as a broad range antiviral agent targeting acidified endosomes. Niclosamide is approved for human use against helminthic infections, and has anti-neoplastic and antiviral effects. Its mode of action is unknown. Here, we show that niclosamide, which is a weak lipophilic acid inhibited infection with pH-dependent human rhinoviruses (HRV) and influenza virus. Structure-activity studies showed that antiviral efficacy and endolysosomal pH neutralization co-tracked, and acidification of the extracellular medium bypassed the virus entry block. Niclosamide did not affect the vacuolar H(+)-ATPase, but neutralized coated vesicles or synthetic liposomes, indicating a proton carrier mode-of-action independent of any protein target. This report demonstrates that physico-chemical interference with host pathways has broad range antiviral effects, and provides a proof of concept for the development of host-directed antivirals.
Assuntos
Antivirais/farmacologia , Endossomos/efeitos dos fármacos , Niclosamida/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Rhinovirus/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Antinematódeos/farmacologia , Vesículas Revestidas/efeitos dos fármacos , Sinergismo Farmacológico , Endossomos/fisiologia , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Lipossomos , Macrolídeos/farmacologia , Niclosamida/química , Orthomyxoviridae/fisiologia , Infecções por Vírus de RNA/tratamento farmacológico , Infecções por Vírus de RNA/prevenção & controle , Rhinovirus/fisiologia , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder characterized by left ventricular hypertrophy, hyperdynamic contraction, and impaired relaxation of the heart. These functional derangements arise directly from altered sarcomeric function due to either mutations in genes encoding sarcomere proteins, or other defects such as abnormal energetics. Current treatment options do not directly address this causal biology but focus on surgical and extra-sarcomeric (sarcolemmal) pharmacological symptomatic relief. Mavacamten (formerly known as MYK-461), is a small molecule designed to regulate cardiac function at the sarcomere level by selectively but reversibly inhibiting the enzymatic activity of myosin, the fundamental motor of the sarcomere. This review summarizes the mechanism and translational progress of mavacamten from proteins to patients, describing how the mechanism of action and pharmacological characteristics, involving both systolic and diastolic effects, can directly target pathophysiological derangements within the cardiac sarcomere to improve cardiac structure and function in HCM. Mavacamten was approved by the Food and Drug Administration in April 2022 for the treatment of obstructive HCM and now goes by the commercial name of Camzyos. Full information about the risks, limitations, and side effects can be found at www.accessdata.fda.gov/drugsatfda_docs/label/2022/214998s000lbl.pdf.
Assuntos
Cardiomiopatia Hipertrófica , Medicina de Precisão , Estados Unidos , Humanos , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/genética , Benzilaminas/efeitos adversos , Benzilaminas/química , MiosinasRESUMO
Hypertrophic cardiomyopathy (HCM) is a chronic, progressive disease of the cardiomyocyte with a diverse and heterogeneous clinical presentation and course. This diversity and heterogeneity have added to the complexity of modeling the pathophysiological pathways that contribute to the disease burden. The development of novel therapeutic approaches targeting precise mechanisms within the underlying biology of HCM provides a tool to model and test these pathways. Here, we integrate the results of clinical observations with mavacamten, an allosteric, selective, and reversible inhibitor of cardiac myosin, the motor unit of the sarcomere, to develop an integrated pathophysiological pathway model of HCM, confirming the key role of excess sarcomeric activity. This model may serve as a foundation to understand the role of HCM pathophysiological pathways in the clinical presentation of the disease, and how a targeted therapeutic intervention capable of normalizing sarcomeric activity and repopulating low-energy utilization states may reduce the impact of these pathways in HCM and potentially related disease states.
Assuntos
Cardiomiopatia Hipertrófica , Benzilaminas/metabolismo , Benzilaminas/uso terapêutico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/metabolismo , Humanos , Sarcômeros/metabolismo , Uracila/análogos & derivados , Uracila/metabolismo , Uracila/uso terapêuticoRESUMO
We report the use of a fragment-based lead discovery method, Tethering with extenders, to discover a pyridinone fragment that binds in an adaptive site of the protein PDK1. With subsequent medicinal chemistry, this led to the discovery of a potent and highly selective inhibitor of PDK1, which binds in the 'DFG-out' conformation.
Assuntos
Desenho de Fármacos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Cristalografia por Raios X , Descoberta de Drogas , Inibidores Enzimáticos/química , Concentração Inibidora 50 , Modelos Biológicos , Estrutura Molecular , Piridonas/química , Piridonas/farmacologia , Piruvato Desidrogenase Quinase de Transferência de Acetil , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-AtividadeRESUMO
BACE-1 (beta-site amyloid precursor protein cleaving enzyme), a prominent target in Alzheimer's disease drug discovery efforts, was surveyed using Tethering technology to discover small molecule fragment ligands that bind to the enzyme active site. Screens of a library of >15000 thiol-containing fragments versus a panel of BACE-1 active site cysteine mutants under redox-controlled conditions revealed several novel amine-containing fragments that could be selectively captured by subsets of the tethering sites. For one such hit class, defined by a central aminobenzylpiperidine (ABP) moiety, X-ray crystal structures of BACE mutant-disulfide conjugates revealed that the fragment bound by engaging both catalytic aspartates with hydrogen bonds. The affinities of ABP fragments were improved by structure-guided chemistry, first for conjugation as thiol-containing fragments and then for stand-alone, noncovalent inhibition of wild-type (WT) BACE-1 activity. Crystallography confirmed that the inhibitors bound in exactly the same mode as the disulfide-conjugated fragments that were originally selected from the screen. The ABP ligands represent a new type of nonpeptidic BACE-1 inhibitor motif that has not been described in the aspartyl protease literature and may serve as a starting point for the development of BACE-1-directed Alzheimer's disease therapeutics.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Descoberta de Drogas/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Biocatálise , Domínio Catalítico , Cisteína , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/metabolismo , Humanos , Ligantes , Modelos Moleculares , Conformação Molecular , Mutação , Peptídeos/química , Piperidinas/química , Piperidinas/metabolismo , Relação Estrutura-AtividadeRESUMO
Compound 1 (SNS-314) is a potent and selective Aurora kinase inhibitor that is currently in clinical trials in patients with advanced solid tumors. This communication describes the synthesis of prodrug derivatives of 1 with improved aqueous solubility profiles. In particular, phosphonooxymethyl-derived prodrug 2g has significantly enhanced solubility and is converted to the biologically active parent (1) following iv as well as po administration to rodents.
Assuntos
Compostos de Fenilureia/química , Pró-Fármacos/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Tiazóis/química , Água/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Aurora Quinases , Masculino , Camundongos , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Solubilidade , Tiazóis/farmacocinética , Tiazóis/farmacologiaRESUMO
This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.
Assuntos
Antineoplásicos/química , Benzimidazóis/química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Aurora Quinases , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Linhagem Celular Tumoral , Humanos , Camundongos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
Obesity and type II diabetes are closely linked metabolic syndromes that afflict >100 million people worldwide. Although protein tyrosine phosphatase 1B (PTP1B) has emerged as a promising target for the treatment of both syndromes, the discovery of pharmaceutically acceptable inhibitors that bind at the active site remains a substantial challenge. Here we describe the discovery of an allosteric site in PTP1B. Crystal structures of PTP1B in complex with allosteric inhibitors reveal a novel site located approximately 20 A from the catalytic site. We show that allosteric inhibitors prevent formation of the active form of the enzyme by blocking mobility of the catalytic loop, thereby exploiting a general mechanism used by tyrosine phosphatases. Notably, these inhibitors exhibit selectivity for PTP1B and enhance insulin signaling in cells. Allosteric inhibition is a promising strategy for targeting PTP1B and constitutes a mechanism that may be applicable to other tyrosine phosphatases.
Assuntos
Proteínas Tirosina Fosfatases/química , Sítio Alostérico , Animais , Sítios de Ligação , Ligação Competitiva , Células CHO , Catálise , Domínio Catalítico , Clonagem Molecular , Cricetinae , Cristalografia por Raios X , DNA/química , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Cinética , Ligantes , Modelos Químicos , Modelos Moleculares , Obesidade , Monoéster Fosfórico Hidrolases/química , Ligação Proteica , Conformação Proteica , Estrutura Terciária de Proteína , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Fatores de Tempo , Transfecção , Tirosina/químicaRESUMO
This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition. In particular, compound 21 (SNS-314) is a potent and selective Aurora kinase inhibitor that exhibits significant activity in pre-clinical in vivo tumor models.
Assuntos
Neoplasias Experimentais/tratamento farmacológico , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Quinazolinas/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Aurora Quinases , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Camundongos , Transplante de Neoplasias , Neoplasias Experimentais/enzimologia , Quinazolinas/química , Relação Estrutura-AtividadeRESUMO
A series of novel beta-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing an aminoethylene (AE) tetrahedral intermediate isostere were synthesized and evaluated in comparison to corresponding hydroxyethylene (HE) compounds. Enzymatic inhibitory values were similar for both isosteres, as were structure-activity relationships with respect to stereochemical preference and substituent variation (P2/P3, P1, and P2'); however, the AE compounds were markedly more potent in a cell-based assay for reduction of beta-secretase activity. The incorporation of preferred P2/P3, P1, and P2' substituents into the AE pharmacophore yielded compound 7, which possessed enzymatic and cell assay IC(50)s of 26 nM and 180 nM, respectively. A three-dimensional crystal structure of 7 in complex with BACE-1 revealed that the amino group of the inhibitor core engages the catalytic aspartates in a manner analogous to hydroxyl groups in HE inhibitors. The AE isostere class represents a promising advance in the development of BACE-1 inhibitors.
Assuntos
Endopeptidases/química , Etilaminas/síntese química , Inibidores de Proteases/síntese química , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Sítios de Ligação , Linhagem Celular , Cristalografia por Raios X , Dipeptídeos/síntese química , Dipeptídeos/química , Dipeptídeos/farmacologia , Etilaminas/química , Etilaminas/farmacologia , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Relação Estrutura-AtividadeRESUMO
Caspase-1, a mediator of the posttranslational processing of IL-1beta and IL-18, requires an aspartic acid in the P1 position of its substrates. The mechanisms of caspase-1 activation remain poorly understood despite numerous structures of the enzyme complexed with aspartate-based inhibitors. Here we report a crystal structure of ligand-free caspase-1 that displays dramatic rearrangements of loops defining the active site to generate a closed conformation that is incompatible with substrate binding. A structure of the enzyme complexed with malonate shows the protein in its open (active-site ligand-bound) conformation in which malonate reproduces the hydrogen bonding network observed in structures with covalent inhibitors. These results illustrate the essential function of the obligatory aspartate recognition element that opens the active site of caspase-1 to substrates and may be the determinant responsible for the conformational changes between ligand-free and -bound forms of the enzyme, and suggest a new approach for identifying novel aspartic acid mimetics.
Assuntos
Ácido Aspártico/química , Caspase 1/química , Malonatos/química , Modelos Moleculares , Proteínas Recombinantes/química , Cristalografia por Raios X , Dimerização , Humanos , Ligação de Hidrogênio , Ligantes , Mutação/genéticaRESUMO
Hypertrophic cardiomyopathy (HCM) is an inherited disease of heart muscle that can be caused by mutations in sarcomere proteins. Clinical diagnosis depends on an abnormal thickening of the heart, but the earliest signs of disease are hyperdynamic contraction and impaired relaxation. Whereas some in vitro studies of power generation by mutant and wild-type sarcomere proteins are consistent with mutant sarcomeres exhibiting enhanced contractile power, others are not. We identified a small molecule, MYK-461, that reduces contractility by decreasing the adenosine triphosphatase activity of the cardiac myosin heavy chain. Here we demonstrate that early, chronic administration of MYK-461 suppresses the development of ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis and attenuates hypertrophic and profibrotic gene expression in mice harboring heterozygous human mutations in the myosin heavy chain. These data indicate that hyperdynamic contraction is essential for HCM pathobiology and that inhibitors of sarcomere contraction may be a valuable therapeutic approach for HCM.
Assuntos
Adenosina Trifosfatases/antagonistas & inibidores , Benzilaminas/administração & dosagem , Miosinas Cardíacas/antagonistas & inibidores , Cardiomiopatia Hipertrófica Familiar/tratamento farmacológico , Contração Miocárdica/efeitos dos fármacos , Cadeias Pesadas de Miosina/antagonistas & inibidores , Sarcômeros/efeitos dos fármacos , Uracila/análogos & derivados , Animais , Benzilaminas/química , Miosinas Cardíacas/genética , Cardiomiopatia Hipertrófica Familiar/patologia , Cardiomiopatia Hipertrófica Familiar/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Fibrose , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Heterozigoto , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Mutação , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Cadeias Pesadas de Miosina/genética , Ratos , Uracila/administração & dosagem , Uracila/químicaRESUMO
A case study of the discovery of small molecule antagonists to the integrins GPIIbIIIa (alphaII(B)beta3), alphavbeta3, LFA-1 (alphaLbeta2), alpha4beta1 and alpha4beta7 is presented from the perspective of a biotechnology research organization. A strategy incorporating protein mutagenesis and structural studies to develop a structure-activity relationship (SAR) that described the 'epitope' of the integrin ligand was crucial to the identification of peptide analogs of these proteins, and subsequently, through parallel trends in SAR, to the identification of small molecule mimetics of these peptides, which are active analogs of the protein ligands themselves.
Assuntos
Integrinas/antagonistas & inibidores , Ligantes , Peptídeos/química , Preparações Farmacêuticas/química , Biotecnologia/tendências , Desenho de Fármacos , Integrinas/química , Antígeno-1 Associado à Função Linfocitária/química , Mimetismo Molecular , Pesquisa/tendênciasRESUMO
Fragment assembly has shown promise for discovering small-molecule antagonists for difficult targets, including protein-protein interactions. Here, we describe a process for identifying a 60 nM inhibitor of the interleukin-2 (IL-2)/IL-2 receptor (IL-2Ralpha) interaction. By use of fragment-based approaches, a compound with millimolar affinity was evolved to a hit series with low micromolar activity, and these compounds were optimized into a lead series with nanomolar affinity. Fragment assembly was useful not only for hit identification, but also for lead optimization. Throughout the discovery process, biophysical methods and structural biology demonstrated that compounds bound reversibly to IL-2 at the IL-2 receptor binding site.
Assuntos
Acetileno/síntese química , Dipeptídeos/síntese química , Interleucina-2/antagonistas & inibidores , Receptores de Interleucina/antagonistas & inibidores , Acetileno/química , Acetileno/farmacologia , Animais , Derivados de Benzeno/química , Sítios de Ligação , Técnicas de Química Combinatória , Cristalografia por Raios X , Dipeptídeos/química , Dipeptídeos/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Interleucina-2/química , Subunidade alfa de Receptor de Interleucina-2 , Camundongos , Modelos Moleculares , Piperidinas/química , Pirazóis/química , Receptores de Interleucina/químicaRESUMO
The design, synthesis, and in vitro activities of a series of potent and selective small-molecule inhibitors of caspase-3 are described. From extended tethering, a salicylic acid fragment was identified as having binding affinity for the S(4) pocket of caspase-3. X-ray crystallography and molecular modeling of the initial tethering hit resulted in the synthesis of 4, which reversibly inhibited caspase-3 with a K(i) = 40 nM. Further optimization led to the identification of a series of potent and selective inhibitors with K(i) values in the 20-50 nM range. One of the most potent compounds in this series, 66b, inhibited caspase-3 with a K(i) = 20 nM and selectivity of 8-500-fold for caspase-3 vs a panel of seven caspases (1, 2, and 4-8). A high-resolution X-ray cocrystal structure of 4 and 66b supports the predicted binding modes of our compounds with caspase-3.
Assuntos
Ácido Aspártico/síntese química , Inibidores de Caspase , Inibidores Enzimáticos/síntese química , Salicilatos/síntese química , Sulfonamidas/síntese química , Ácido Aspártico/análogos & derivados , Ácido Aspártico/química , Benzoxazóis/síntese química , Benzoxazóis/química , Sítios de Ligação , Caspase 3 , Caspases/química , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/química , Fluorenos/síntese química , Fluorenos/química , Humanos , Ligação Proteica , Salicilatos/química , Sulfonamidas/química , Tiofenos/síntese química , Tiofenos/químicaRESUMO
This article provides an overview of methods for reliability assessment of quantitative structure-activity relationship (QSAR) models in the context of regulatory acceptance of human health and environmental QSARs. Useful diagnostic tools and data analytical approaches are highlighted and exemplified. Particular emphasis is given to the question of how to define the applicability borders of a QSAR and how to estimate parameter and prediction uncertainty. The article ends with a discussion regarding QSAR acceptability criteria. This discussion contains a list of recommended acceptability criteria, and we give reference values for important QSAR performance statistics. Finally, we emphasize that rigorous and independent validation of QSARs is an essential step toward their regulatory acceptance and implementation.
Assuntos
Exposição Ambiental , Relação Quantitativa Estrutura-Atividade , Reprodutibilidade dos Testes , Europa (Continente) , Regulamentação Governamental , Humanos , Modelos Teóricos , Reconhecimento Automatizado de Padrão , Análise de Regressão , Estados UnidosRESUMO
Potent imidazopyridine-based inhibitors of fatty acid synthase (FASN) are described. The compounds are shown to have antiviral (HCV replicon) activities that track with their biochemical activities. The most potent analogue (compound 19) also inhibits rat FASN and inhibits de novo palmitate synthesis in vitro (cell-based) as well as in vivo.
RESUMO
BACKGROUND: Topoisomerase II is critical for DNA replication, transcription and chromosome segregation and is a well validated target of anti-neoplastic drugs including the anthracyclines and epipodophyllotoxins. However, these drugs are limited by common tumor resistance mechanisms and side-effect profiles. Novel topoisomerase II-targeting agents may benefit patients who prove resistant to currently available topoisomerase II-targeting drugs or encounter unacceptable toxicities. Voreloxin is an anticancer quinolone derivative, a chemical scaffold not used previously for cancer treatment. Voreloxin is completing Phase 2 clinical trials in acute myeloid leukemia and platinum-resistant ovarian cancer. This study defined voreloxin's anticancer mechanism of action as a critical component of rational clinical development informed by translational research. METHODS/PRINCIPAL FINDINGS: Biochemical and cell-based studies established that voreloxin intercalates DNA and poisons topoisomerase II, causing DNA double-strand breaks, G2 arrest, and apoptosis. Voreloxin is differentiated both structurally and mechanistically from other topoisomerase II poisons currently in use as chemotherapeutics. In cell-based studies, voreloxin poisoned topoisomerase II and caused dose-dependent, site-selective DNA fragmentation analogous to that of quinolone antibacterials in prokaryotes; in contrast etoposide, the nonintercalating epipodophyllotoxin topoisomerase II poison, caused extensive DNA fragmentation. Etoposide's activity was highly dependent on topoisomerase II while voreloxin and the intercalating anthracycline topoisomerase II poison, doxorubicin, had comparable dependence on this enzyme for inducing G2 arrest. Mechanistic interrogation with voreloxin analogs revealed that intercalation is required for voreloxin's activity; a nonintercalating analog did not inhibit proliferation or induce G2 arrest, while an analog with enhanced intercalation was 9.5-fold more potent. CONCLUSIONS/SIGNIFICANCE: As a first-in-class anticancer quinolone derivative, voreloxin is a toposiomerase II-targeting agent with a unique mechanistic signature. A detailed understanding of voreloxin's molecular mechanism, in combination with its evolving clinical profile, may advance our understanding of structure-activity relationships to develop safer and more effective topoisomerase II-targeted therapies for the treatment of cancer.
Assuntos
DNA Topoisomerases Tipo II/efeitos dos fármacos , DNA/metabolismo , Naftiridinas/farmacologia , Quinolonas/química , Tiazóis/farmacologia , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Dano ao DNA , Fragmentação do DNA/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Etoposídeo/farmacologia , Fase G2 , Humanos , Substâncias Intercalantes , Naftiridinas/uso terapêutico , Quinolonas/farmacologia , Tiazóis/uso terapêuticoAssuntos
Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Animais , Cristalografia por Raios X , Inibidores Enzimáticos/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Peso Molecular , Ligação Proteica , Relação Estrutura-Atividade , Tecnologia FarmacêuticaRESUMO
The identification, design, and synthesis of a series of novel sulfamide- and urea-based small-molecule antagonists of the protein-protein interaction IL-2/IL-2Ralpha are described. Installation of a furan carboxylic acid fragment onto a low-micromolar sulfamide resulted in a 23-fold improvement in activity, providing a sub-micromolar, nonpeptidic IL-2 inhibitor (IC(50)=0.60 microM).