RESUMEN
The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as central nodes within this pathway. The feasibility of targeting the RAS/MAPK pathway has been demonstrated by the clinical responses observed through the use of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however, resistance frequently develops. Importantly, ERK1/2 inhibition may have clinical utility in overcoming acquired resistance to RAF and MEK inhibitors, where RAS/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K melanoma. We describe our structure-based design approach leading to the discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364 exhibits high cellular potency (IC50 = 6 nM) as well as excellent physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging antitumor activity in preclinical models.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Descubrimiento de Drogas , Imidazoles/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirazinas/uso terapéutico , Pirimidinas/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular , Quimioterapia Combinada , Femenino , Humanos , Imidazoles/farmacología , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Estructura Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirazinas/farmacología , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations. In vivo, the combination of compound 28 and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.
Asunto(s)
Antineoplásicos/farmacología , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Cristalografía por Rayos X , Perros , Femenino , Humanos , Quinasas Asociadas a Receptores de Interleucina-1/química , Linfoma de Células B Grandes Difuso/genética , Espectroscopía de Resonancia Magnética , Masculino , Ratones SCID , Mutación , Factor 88 de Diferenciación Mieloide/genética , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/química , Pirroles/química , Ratas Wistar , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
There are a number of small-molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway that have either been approved or are in clinical development for oncology across a range of disease indications. The inhibition of ERK1/2 is of significant current interest, as cell lines with acquired resistance to BRAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition in preclinical models. This article reports on our recent work to identify novel, potent, and selective reversible ERK1/2 inhibitors from a low-molecular-weight, modestly active, and highly promiscuous chemical start point, compound 4. To guide and inform the evolution of this series, inhibitor binding mode information from X-ray crystal structures was critical in the rapid exploration of this template to compound 35, which was active when tested in in vivo antitumor efficacy experiments.
Asunto(s)
Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Perros , Descubrimiento de Drogas , Humanos , Metilación , Inhibidores de Proteínas Quinasas/farmacocinéticaRESUMEN
Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds, leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subsequent optimization to improve the overall profile, specifically with regard to hERG activity, led to alkyl sulfone 16. This compound did not cause tonic-clonic convulsions in mice, had a good pharmacokinetic profile, and displayed in vivo efficacy in murine models. Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119.
Asunto(s)
Epilepsia Tónico-Clónica/prevención & control , Oxadiazoles/farmacocinética , Pirimidinas/farmacocinética , Receptores Acoplados a Proteínas G/agonistas , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Perros , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Femenino , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Oxadiazoles/química , Oxadiazoles/uso terapéutico , Pirimidinas/química , Pirimidinas/uso terapéutico , Relación Estructura-ActividadRESUMEN
Rational structure-based design has yielded highly potent inhibitors of cathepsin K (Cat K) with excellent physical properties, selectivity profiles, and pharmacokinetics. Compounds with a 3,4-(CH3O)2Ph motif, such as 31, were found to have excellent metabolic stability and absorption profiles. Through metabolite identification studies, a reactive metabolite risk was identified with this motif. Subsequent structure-based design of isoteres culminated in the discovery of an optimized and balanced inhibitor (indazole, 38).
Asunto(s)
Catepsina K/antagonistas & inhibidores , Ciclohexanos/síntesis química , Indazoles/síntesis química , Animales , Proteínas Sanguíneas/metabolismo , Células Cultivadas , Ciclohexanos/farmacocinética , Ciclohexanos/farmacología , Diseño de Fármacos , Hepatocitos/metabolismo , Humanos , Indazoles/farmacocinética , Indazoles/farmacología , Masculino , Modelos Moleculares , Unión Proteica , Ratas , Ratas Wistar , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The discovery of nitrile compound 4, a potent inhibitor of Cathepsin K (Cat K) with good bioavailability in dog is described. The compound was used to demonstrate target engagement and inhibition of Cat K in an in vivo dog PD model. The margin to hERG ion channel inhibition was deemed too low for a clinical candidate and an optimisation program to find isosteres or substitutions on benzothiazole group led to the discovery of 20, 24 and 27; all three free from hERG inhibition.
Asunto(s)
Benzotiazoles/química , Benzotiazoles/farmacología , Catepsina K/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Nitrilos/química , Nitrilos/farmacología , Animales , Benzotiazoles/metabolismo , Benzotiazoles/farmacocinética , Catepsina K/metabolismo , Perros , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Nitrilos/metabolismo , Nitrilos/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.
Asunto(s)
Carbolinas/farmacología , Catepsina K/antagonistas & inhibidores , Indoles/farmacología , Osteoartritis/tratamiento farmacológico , Inhibidores de Proteasas/farmacología , Animales , Carbolinas/metabolismo , Carbolinas/farmacocinética , Carbolinas/uso terapéutico , Catepsina K/química , Perros , Humanos , Indoles/metabolismo , Indoles/farmacocinética , Indoles/uso terapéutico , Concentración 50 Inhibidora , Masculino , Modelos Moleculares , Osteoartritis/enzimología , Inhibidores de Proteasas/metabolismo , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/uso terapéutico , Conformación Proteica , Ratas , Especificidad por SustratoRESUMEN
G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, 2, into a development candidate, 42. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism.
Asunto(s)
Oxadiazoles/síntesis química , Piridinas/síntesis química , Receptores Acoplados a Proteínas G/agonistas , Animales , Disponibilidad Biológica , Carbamatos/síntesis química , Carbamatos/química , Carbamatos/farmacología , Cristalografía por Rayos X , Perros , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Moleculares , Estructura Molecular , Oxadiazoles/química , Oxadiazoles/farmacología , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacología , Piridinas/química , Piridinas/farmacología , Ratas , Ratas Wistar , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Bibliotecas de Moléculas Pequeñas , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/química , Sulfonas/farmacologíaRESUMEN
A novel N-aryl piperazine-1-carboxamide series of human CCR2 chemokine receptor antagonists was discovered. Early analogues were potent at CCR2 but also inhibited the hERG cardiac ion channel. Structural modifications which decreased lipophilicity and basicity resulted in the identification of a sub-series with an improved margin over hERG. The pharmacological and pharmacokinetic properties of the lead compound from this series, N-(3,4-dichlorophenyl)-4-[(2R)-4-isopropylpiperazine-2-carbonyl]piperazine-1-carboxamide, are described.
Asunto(s)
Antiinflamatorios/síntesis química , Piperazinas/síntesis química , Receptores CCR2/antagonistas & inhibidores , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Calcio/metabolismo , Perros , Diseño de Fármacos , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Inflamación/tratamiento farmacológico , Piperazinas/farmacocinética , Piperazinas/farmacología , Unión Proteica , Ratas , Receptores CCR2/metabolismoRESUMEN
Investigation of weak screening hits led to the identification of N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-2-phenylacetamides and N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-N'-benzylureas as potent, selective ligands for the human CCR5 chemokine receptor.