RESUMEN
Antagonism of CCR9 is a promising mechanism for treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease. There is limited experimental data on CCR9 and its ligands, complicating efforts to identify new small molecule antagonists. We present here results of a successful virtual screening and rational hit-to-lead campaign that led to the discovery and initial optimization of novel CCR9 antagonists. This work uses a novel data fusion strategy to integrate the output of multiple computational tools, such as 2D similarity search, shape similarity, pharmacophore searching, and molecular docking, as well as the identification and incorporation of privileged chemokine fragments. The application of various ranking strategies, which combined consensus and parallel selection methods to achieve a balance of enrichment and novelty, resulted in 198 virtual screening hits in total, with an overall hit rate of 18%. Several hits were developed into early leads through targeted synthesis and purchase of analogs.
Asunto(s)
Simulación por Computador , Simulación del Acoplamiento Molecular/métodos , Receptores CCR/agonistas , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Ligandos , Estructura Molecular , Análisis de Componente Principal , Receptores CXCR4/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-ActividadRESUMEN
The emergence and spread of multidrug-resistant (MDR) Gram negative bacteria presents a serious threat for public health. Novel antimicrobials that could overcome the resistance problems are urgently needed. UDP-3-O-(R-3-hydroxymyristol)-N-acetylglucosamine deacetylase (LpxC) is a cytosolic zinc-based deacetylase that catalyzes the first committed step in the biosynthesis of lipid A, which is essential for the survival of Gram-negative bacteria. Our efforts toward the discovery of novel LpxC inhibitors are presented herein.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/química , Antibacterianos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/enzimología , Amidohidrolasas/metabolismo , Descubrimiento de Drogas , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Humanos , Simulación del Acoplamiento MolecularRESUMEN
Irritable bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC) are serious chronic diseases affecting millions of patients worldwide. Studies of human chemokine biology has suggested C-C chemokine receptor 9 (CCR9) may be a key mediator of pro-inflammatory signaling. Discovery of agents that inhibit CCR9 may lead to new therapies for CD and UC patients. Herein we describe the evolution of a high content screening hit (1) into potent inhibitors of CCR9, such as azaindole 12.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Descubrimiento de Drogas , Indoles/farmacología , Receptores CCR/antagonistas & inhibidores , Colitis Ulcerosa/metabolismo , Enfermedad de Crohn/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Indoles/síntesis química , Indoles/química , Estructura Molecular , Receptores CCR/metabolismo , Relación Estructura-ActividadRESUMEN
Inhibitors of the ATPase function of bacterial DNA gyrase, located in the GyrB subunit and its related ParE subunit in topoisomerase IV, have demonstrated antibacterial activity. In this study we describe an NMR fragment-based screening effort targeting Staphylococcus aureus GyrB that identified several attractive and novel starting points with good ligand efficiency. Fragment hits were further characterized using NMR binding studies against full-length S. aureus GyrB and Escherichia coli ParE. X-ray co-crystal structures of select fragment hits confirmed binding and suggested a path for medicinal chemistry optimization. The identification, characterization, and elaboration of one of these fragment series to a 0.265 µM inhibitor is described herein.
Asunto(s)
Antibacterianos/química , Proteínas Bacterianas/antagonistas & inhibidores , Girasa de ADN/química , Inhibidores de Topoisomerasa II/química , Adenosina Trifosfatasas/metabolismo , Antibacterianos/metabolismo , Proteínas Bacterianas/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/antagonistas & inhibidores , Topoisomerasa de ADN IV/metabolismo , Diseño de Fármacos , Escherichia coli/metabolismo , Ligandos , Espectroscopía de Resonancia Magnética , Simulación de Dinámica Molecular , Unión Proteica , Estructura Terciaria de Proteína , Staphylococcus aureus/enzimología , Inhibidores de Topoisomerasa II/metabolismoRESUMEN
Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, affects millions of people worldwide. CCR9 has been shown to be a key chemokine receptor mediating the local inflammatory responses in the GI tract. The CCR9 inhibitor Vercirnon advanced to phase 3 clinical trials, but carries several liabilities which we sought to improve.
Asunto(s)
Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Receptores CCR/antagonistas & inhibidores , Sulfonamidas/química , Sulfonamidas/farmacología , Animales , Técnicas de Química Sintética , Evaluación Preclínica de Medicamentos/métodos , Humanos , Concentración 50 Inhibidora , Ratones , Relación Estructura-ActividadRESUMEN
Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling of the small pulmonary arteries (PA) and progressive increase in pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Although several drugs are approved for the treatment of PAH, mortality remains high. Accumulating evidence supports a pathological function of integrins in vessel remodeling, which are gaining renewed interest as drug targets. However, their role in PAH remains largely unexplored. We found that the arginine-glycine-aspartate (RGD)-binding integrin α5ß1 is upregulated in PA endothelial cells (PAEC) and PA smooth muscle cells (PASMC) from PAH patients and remodeled PAs from animal models. Blockade of the integrin α5ß1 or depletion of the α5 subunit resulted in mitotic defects and inhibition of the pro-proliferative and apoptosis-resistant phenotype of PAH cells. Using a novel small molecule integrin inhibitor and neutralizing antibodies, we demonstrated that α5ß1 integrin blockade attenuates pulmonary vascular remodeling and improves hemodynamics and RV function in multiple preclinical models. Our results provide converging evidence to consider α5ß1 integrin inhibition as a promising therapy for pulmonary hypertension. One sentence summary: The α5ß1 integrin plays a crucial role in pulmonary vascular remodeling.
RESUMEN
Previous drug discovery efforts identified classical PYK2 kinase inhibitors such as 2 and 3 that possess selectivity for PYK2 over its intra-family isoform FAK. Efforts to identify more kinome-selective chemical matter that stabilize a DFG-out conformation of the enzyme are described herein. Two sub-series of PYK2 inhibitors, an indole carboxamide-urea and a pyrazole-urea have been identified and found to have different binding interactions with the hinge region of PYK2. These leads proved to be more selective than the original classical inhibitors.
Asunto(s)
Quinasa 2 de Adhesión Focal/antagonistas & inhibidores , Indoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Urea/farmacología , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Quinasa 2 de Adhesión Focal/metabolismo , Células HEK293 , Humanos , Indoles/síntesis química , Indoles/química , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Ratas , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/químicaRESUMEN
Based on a high throughput screening hit, pyrrolopyrimidine inhibitors of the Akt kinase are explored. X-ray co-crystal structures of two lead series results in the understanding of key binding interactions, the design of new lead series, and enhanced potency. The syntheses of these series and their biological activities are described. Spiroindoline 13j is found to have an Akt1 kinase IC(50) of 2.4+/-0.6 nM, Akt cell potency of 50+/-19 nM, and provides 68% inhibition of tumor growth in a mouse xenograft model (50 mg/kg, qd, po).
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirimidinas/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Animales , Antineoplásicos/química , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Diseño de Fármacos , Concentración 50 Inhibidora , Ratones , Conformación Molecular , Estructura Molecular , Pirimidinas/química , Pirroles/química , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
The ATPase subunit of DNA gyrase B is an attractive antibacterial target due to high conservation across bacteria and the essential role it plays in DNA replication. A novel class of pyrazolopyridone inhibitors was discovered by optimizing a fragment screening hit scaffold using structure guided design. These inhibitors show potent Gram-positive antibacterial activity and low resistance incidence against clinically important pathogens.
RESUMEN
The Hedgehog (Hh) signaling pathway directs the development of multiple tissues during embryonic development, and contributes to tissue homeostasis in adults. Deficient Hh signaling results in defective embryogenesis; conversely, excessive Hh signaling is associated with an inherited cancer predisposition syndrome (Gorlin Syndrome), and a growing list of sporadic human cancers. It is now clear that multiple components of "The Hh Pathway" can be altered in tumors. The Hhs are morphogens that signal through effectors that are largely unprecedented in drug discovery, with many key concepts derived from studies in Drosophila melanogaster. However, studies in tumor cell lines have recently identified targets that can be exploited for the discovery of human Hh antagonists, with additional targets likely to emerge as the human pathway is further defined. Here, we review basic aspects of Hh signal transduction, with an emphasis on molecular targets for drug discovery. The use of first-generation Hh antagonists such as cyclopamine will also be discussed; such agents remain invaluable in ongoing efforts to validate drug discovery assays and survey tumor lines for Hh dependence. The various types and frequencies of Hh signaling defects in different human tumors will also be reviewed, as will the status of medicinal chemistry efforts to discover novel Hh antagonists. In section VI, we review assays from the literature that could be utilized to discover new Hh antagonists for the treatment of cancer.
Asunto(s)
Antineoplásicos/farmacología , Transducción de Señal/fisiología , Transactivadores/fisiología , Animales , Diseño de Fármacos , Proteínas Hedgehog , Humanos , Transducción de Señal/efectos de los fármacos , Transactivadores/antagonistas & inhibidoresRESUMEN
The emergence and spread of multidrug resistant bacteria are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the discovery of azaindole ureas as a novel class of bacterial gyrase B inhibitors and detail the story of their evolution from a de novo design hit based on structure-based drug design. These inhibitors show potent minimum inhibitory concentrations against fluoroquinolone resistant MRSA and other Gram-positive bacteria.
Asunto(s)
Proteínas Bacterianas/antagonistas & inhibidores , Girasa de ADN/metabolismo , Indoles/farmacología , Staphylococcus aureus Resistente a Meticilina/enzimología , Inhibidores de Topoisomerasa II/farmacología , Urea/farmacología , Proteínas Bacterianas/metabolismo , Cristalografía por Rayos X , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/enzimología , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Indoles/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Modelos Moleculares , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Inhibidores de Topoisomerasa II/química , Urea/análogos & derivadosRESUMEN
Antibacterials with a novel mechanism of action offer a great opportunity to combat widespread antimicrobial resistance. Bacterial DNA Gyrase is a clinically validated target. Through physiochemical property optimization of a pyrazolopyridone hit, a novel class of GyrB inhibitors were discovered. Guided by structure-based drug design, indazole derivatives with excellent enzymatic and antibacterial activity as well as great animal efficacy were discovered.
RESUMEN
This paper describes the design and synthesis of novel, ATP-competitive Akt inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include the discovery of an initial lead that was modestly selective and medicinal chemistry optimization of that lead to provide more selective analogues. Analysis of the data suggested that highly lipophilic analogues would likely suffer from poor overall properties. Central to the discussion is the concept of optimization of lipophilic efficiency and the ability to balance overall druglike propeties with the careful control of lipophilicity in the lead series. Discovery of the nonracemic amide series and subsequent modification produced an advanced analogue that performed well in advanced preclinical assays, including xenograft tumor growth inhibition studies, and this analogue was nominated for clinical development.
Asunto(s)
Adenosina Trifosfato/fisiología , Amidas/síntesis química , Aminoquinolinas/síntesis química , Antineoplásicos/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Amidas/farmacocinética , Amidas/farmacología , Aminoquinolinas/farmacocinética , Aminoquinolinas/farmacología , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Perros , Ratones , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The synthesis and biological evaluation of potent and selective inhibitors of the erbB2 kinase is presented. Based on the 4-anilinoquinazoline chemotype, the syntheses of several new series of erbB2 inhibitors are described with quinazoline and pyrido[4,3-d]pyrimidine cores. The vast majority of these compounds are found to be >100x selective over the closely related EGFR kinase. Two lead compounds are further shown to have low clearance and moderate bioavailability in rat.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias de la Mama/enzimología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Compuestos de Anilina/síntesis química , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Antineoplásicos/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Humanos , Inhibidores de Proteínas Quinasas/síntesis química , Quinazolinas/síntesis química , Quinazolinas/química , Quinazolinas/farmacología , Relación Estructura-ActividadRESUMEN
The design, synthesis, and biological evaluation of potent inhibitors of the TrkA kinase is presented. A homology model is created to aid in the enhancement of potency and selectivity of isothiazole inhibitors found during a high-throughput screen. Three different syntheses are utilized to make diverse analogs within this series. Aminoheterocycles are found to be good urea surrogates, whereas bicyclic substituents on the C3 thio group were found to be extremely potent TrkA inhibitors in kinase and cell assays.
Asunto(s)
Simulación por Computador , Inhibidores Enzimáticos , Receptor trkA/antagonistas & inhibidores , Tiazoles , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
Macrocycle 1 is a new highly potent analogue of bryostatin 1, a promising anti-cancer agent currently in human clinical trials. In vitro, 1 displays picomolar affinity for PKC and exhibits over 100-fold greater potency than bryostatin 1 when tested against various human cancer cell lines. Macrocycle 1 can be generated in clinically required amounts by chemical synthesis in only 19 steps (LLS) and represents a new clinical lead for the treatment of cancer.