RESUMEN
The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.
Asunto(s)
Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Adenosina Trifosfato/metabolismo , Administración Oral , Animales , Sitios de Unión , Disponibilidad Biológica , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/administración & dosificación , Humanos , Enlace de Hidrógeno , Isoenzimas/antagonistas & inhibidores , Ratones Endogámicos C57BL , Esclerosis Múltiple/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Ftalimidas/química , Relación Estructura-ActividadRESUMEN
While several therapeutic options exist, the need for more effective, safe, and convenient treatment for a variety of autoimmune diseases persists. Targeting the Janus tyrosine kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function associated with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. We screened our compound library against JAK3, a key signaling kinase in immune cells, and identified multiple scaffolds showing good inhibitory activity for this kinase. A particular scaffold of interest, the 1H-pyrrolo[2,3-b]pyridine series (7-azaindoles), was selected for further optimization in part on the basis of binding affinity (Ki) as well as on the basis of cellular potency. Optimization of this chemical series led to the identification of VX-509 (decernotinib), a novel, potent, and selective JAK3 inhibitor, which demonstrates good efficacy in vivo in the rat host versus graft model (HvG). On the basis of these findings, it appears that VX-509 offers potential for the treatment of a variety of autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Compuestos Heterocíclicos con 2 Anillos/química , Janus Quinasa 3/antagonistas & inhibidores , Valina/análogos & derivados , Animales , Línea Celular , Bases de Datos de Compuestos Químicos , Perros , Femenino , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/inmunología , Haplorrinos , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Compuestos Heterocíclicos con 2 Anillos/farmacología , Humanos , Janus Quinasa 2/química , Janus Quinasa 3/química , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos CBA , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Ratas , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Valina/química , Valina/farmacocinética , Valina/farmacologíaRESUMEN
A high-throughput screen of our compound archive revealed a novel class of dual FMS-like tyrosine kinase 3 (FLT3)/c-KIT inhibitors. With the help of molecular modeling, this class was rapidly optimized for both potency against FLT3 and FLT3/c-KIT and excellent potency in cell-based assays, leading to dose-dependent cell death in acute myelogenous leukemia (AML) patient blast samples. Ultimately, the AML patient blast data defined the preferred target profile as we designed and evaluated a set of FLT3 selective and FLT3/c-KIT dual molecules. Further optimization for pharmacokinetic properties resulted in the selection of the dual FLT3/c-KIT inhibitor, N(3)-(4-(trans-4-morpholinocyclohexyl)phenyl)-1-(pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine, VX-322 (compound 37), to move forward to preclinical evaluation.
Asunto(s)
Antineoplásicos/síntesis química , Leucemia Mieloide Aguda/patología , Morfolinas/síntesis química , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Triazoles/síntesis química , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Enlace de Hidrógeno , Inyecciones Intravenosas , Leucemia Mieloide Aguda/tratamiento farmacológico , Macaca fascicularis , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Morfolinas/farmacocinética , Morfolinas/farmacología , Unión Proteica , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Triazoles/farmacocinética , Triazoles/farmacologíaRESUMEN
Pictet-Spengler condensation of aldehydes or alpha-keto-esters with 4-(2-anilinophenyl)-7-azaindole (11) or deazapurine (12) gave high yields of the 3,4-fused cyclic compounds. SAR studies, by varying the substituted benzaldehyde components, lead to the discovery of a series of potent JAK2 kinase inhibitors.
Asunto(s)
Indoles/química , Janus Quinasa 2/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Purinas/química , Benzaldehídos/química , Sitios de Unión , Línea Celular , Cristalografía por Rayos X , Descubrimiento de Drogas , Humanos , Janus Quinasa 2/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-ActividadRESUMEN
The synthesis and characterization of a novel polycyclic azaindole based derivative is disclosed, and its binding to JAK2 is described. The compound is further evaluated for its ability to block the EPO/JAK2 signaling cascade in vitro and in vivo.
Asunto(s)
Compuestos Aza/química , Compuestos Aza/farmacología , Indoles/química , Indoles/farmacología , Janus Quinasa 2/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Animales , Compuestos Aza/síntesis química , Compuestos Aza/farmacocinética , Línea Celular Tumoral , Cristalografía por Rayos X , Eritropoyetina/metabolismo , Indoles/síntesis química , Indoles/farmacocinética , Janus Quinasa 2/metabolismo , Lactamas Macrocíclicas/síntesis química , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacocinética , Lactamas Macrocíclicas/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Modelos Moleculares , Conformación Molecular , Conformación Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
Constitutive activation of the EPO/JAK2 signaling cascade has recently been implicated in a variety of myeloproliferative disorders including polycythemia vera, essential thrombocythemia and myelofibrosis. In an effort to uncover therapeutic potential of blocking the EPO/JAK2 signaling cascade, we sought to discover selective inhibitors that block the kinase activity of JAK2. Herein, we describe the discovery and structure based optimization of a novel series of 2-amino-pyrazolo[1,5-a]pyrimidines that exhibit potent inhibition of JAK2.
Asunto(s)
Janus Quinasa 2/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Cristalografía por Rayos X , Descubrimiento de Drogas , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/química , Transducción de Señal/efectos de los fármacos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of substituted 3-aryl-6-amino-triazolo[4,3-b]pyridazines were identified as highly selective inhibitors of Pim-1 kinase. Initial exploration identified compound 24 as a potent, selective inhibitor, limited in its utility by poor solubility and permeability. Understanding the unusual ATP-binding site of the Pim kinases and X-ray crystallographic data on compound 24 led to design improvements in this class of inhibitor. This resulted in compound 29, a selective, soluble and permeable inhibitor of Pim-1.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Piridazinas/química , Triazoles/química , Animales , Línea Celular , Cristalografía por Rayos X , Perros , Diseño de Fármacos , Permeabilidad , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Piridazinas/síntesis química , Piridazinas/farmacología , Solubilidad , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/farmacologíaRESUMEN
To supplement the hits from a high throughput screen, docking was performed against Pim-1 kinase. Glide docking was augmented with a filter to require traditional or aromatic CH..O hydrogen bonds to the kinase hinge. Four diverse actives, of 96 molecules assayed, had K(i) values between 0.091 and 4.5 microM. This gives a 14-fold enrichment over the earlier HTS run, and the two crystal structures solved confirmed the binding modes predicted by docking.
Asunto(s)
Simulación por Computador , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Aryl CH hydrogen bonds play an important role in the binding of several analogues of a pyrazol-3-ylquinazolin-4-ylamine inhibitor of glycogen synthase kinase 3 (GSK3). Understanding the importance of these CH...O and CH...N hydrogen bonds allowed the design of a novel quinazolin-4-ylthiazol-2-ylamine inhibitor of GSK3 with a structurally confirmed CH...O hydrogen bond to the protein.
Asunto(s)
Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/química , Quinazolinas/síntesis química , Tiazoles/síntesis química , Diseño de Fármacos , Enlace de Hidrógeno , Isomerismo , Ligandos , Modelos Moleculares , Conformación Molecular , Quinazolinas/química , Relación Estructura-Actividad , Tiazoles/químicaRESUMEN
In this work we describe BREED, a method for the generation of novel inhibitors from structures of known ligands bound to a common target. The method is essentially an automation of the common medicinal chemistry practice of joining fragments of two known ligands to generate a new inhibitor. The ligand-bound target structures are overlaid, all overlapping bonds in all pairs of ligands are found, and the fragments on each side of each matching bond are swapped to generate the new molecules. Since the method is automated, it can be applied recursively to generate all possible combinations of known ligands. In an application of this method to HIV protease inhibitors and protein kinase inhibitors, hundreds of new molecular structures were generated. These included known inhibitor scaffolds not included in the initial set, entirely novel scaffolds, and novel substituents on known scaffolds. The method is fast, and since all of the ligand functional groups are known to bind the target in the precise position and orientation present in the novel ligand, the success rate of this method should be superior to more traditional de novo design techniques. In an era of increasingly high-throughput structural biology, such methods for high-throughput utilization of structural information will become increasingly valuable.
Asunto(s)
Ciclinas/química , Inhibidores Enzimáticos/química , Proteasa del VIH/química , Proteínas Quinasas Activadas por Mitógenos/química , Cristalización , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/antagonistas & inhibidores , Inhibidores de la Proteasa del VIH/química , Ligandos , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
Although the hydrogen bond is known to be an important mediator of intermolecular interactions, there has yet to be an analysis of the role of CH...O hydrogen bonds in protein-ligand complexes. In this work, we present evidence for such nonstandard hydrogen bonds from a survey of aromatic ligands in 184 kinase crystal structures and 358 high-resolution structures from the Protein Data Bank. CH groups adjacent to the positively charged nitrogen of nicotinamide exhibit geometric preferences strongly suggestive of hydrogen bonding interactions, as do heterocyclic CH groups in kinase ligands, while other aromatic CH groups do not exhibit these characteristics. Ab initio calculations reveal a considerable range of CH...O hydrogen bonding potentials among different aromatic ring systems, with nicotinamide and heterocycles preferred in kinase inhibitors showing particularly favorable interactions. These results provide compelling evidence for the existence of CH...O hydrogen bonds in protein-ligand interactions, as well as information on the relative strength of various aromatic CH donors. Such knowledge will be of considerable value in protein modeling, ligand design, and structure-activity analysis.