RESUMEN
The inhibition of ataxia-telangiectasia mutated (ATM) has been shown to chemo- and radio-sensitize human glioma cells in vitro and therefore might provide an exciting new paradigm in the treatment of glioblastoma multiforme (GBM). The effective treatment of GBM will likely require a compound with the potential to efficiently cross the blood-brain barrier (BBB). Starting from clinical candidate AZD0156, 4, we investigated the imidazoquinolin-2-one scaffold with the goal of improving likely CNS exposure in humans. Strategies aimed at reducing hydrogen bonding, basicity, and flexibility of the molecule were explored alongside modulating lipophilicity. These studies identified compound 24 (AZD1390) as an exceptionally potent and selective inhibitor of ATM with a good preclinical pharmacokinetic profile. 24 showed an absence of human transporter efflux in MDCKII-MDR1-BCRP studies (efflux ratio <2), significant BBB penetrance in nonhuman primate PET studies (Kp,uu 0.33) and was deemed suitable for development as a clinical candidate to explore the radiosensitizing effects of ATM in intracranial malignancies.
Asunto(s)
Ataxia Telangiectasia , Glioblastoma , Piridinas , Quinolonas , Animales , Humanos , Barrera Hematoencefálica/metabolismo , Ataxia Telangiectasia/tratamiento farmacológico , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Neoplasias , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Glioblastoma/tratamiento farmacológicoRESUMEN
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
We report the discovery of a novel series of 3-cinnoline carboxamides as highly potent and selective ataxia telangiectasia mutated (ATM) kinase inhibitors. Optimization of this series focusing on potency and physicochemical properties (especially permeability) led to the identification of compound 21, a highly potent ATM inhibitor (ATM cell IC50 0.0028 µM) with excellent kinase selectivity and favorable physicochemical and pharmacokinetics properties. In vivo, 21 in combination with irinotecan showed tumor regression in the SW620 colorectal tumor xenograft model, superior inhibition to irinotecan alone. Compound 21 was selected for preclinical evaluation alongside AZD0156.
RESUMEN
ATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (<50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution). These efforts resulted in the discovery of 64 (AZD0156), an exceptionally potent and selective inhibitor of ATM based on an imidazo[4,5- c]quinolin-2-one core. 64 has good preclinical phamacokinetics, a low predicted clinical dose, and a high maximum absorbable dose. 64 has been shown to potentiate the efficacy of the approved drugs irinotecan and olaparib in disease relevant mouse models and is currently undergoing clinical evaluation with these agents.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Diseño de Fármacos , Piridinas/farmacocinética , Quinolinas/farmacocinética , Quinolonas/farmacología , Quinolonas/farmacocinética , Administración Oral , Proteínas de la Ataxia Telangiectasia Mutada/química , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Disponibilidad Biológica , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Conformación Proteica , Inhibidores de Proteínas Quinasas , Piridinas/administración & dosificación , Piridinas/química , Quinolinas/administración & dosificación , Quinolinas/química , Quinolonas/administración & dosificación , Quinolonas/química , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
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
Two new o-hydroxycinnamates have been prepared for photoremovable protecting groups, and their photochemistry has been investigated. The photolysis of two caged compounds can efficiently release the corresponding alcohol in aqueous solutions, and the uncaging reaction proceeds with large one-photon excitation cross sections (1919 and 1535 M(-1) cm(-1)). The uncaging process has been observed by NMR spectroscopy. The caged compounds exhibit good aqueous solubility and excellent resistance to hydrolysis in a buffer solution.
Asunto(s)
Alcoholes/química , Ácidos Cumáricos/química , Fluorescencia , Agua/química , Ácidos Cumáricos/síntesis química , Estructura Molecular , Fotoquímica , Fotólisis , SolubilidadRESUMEN
The [2 + 2] photochemical cycloadditions (the Paternò-Büchi reaction) of 5- or/and 6-methyl substituted uracil derivatives with 4,4'-disubstituted benzophenones generate two series of regioisomeric oxetanes, 3 and 4. The regioselectivity (3/4) and the photochemical efficiency are strongly dependent on methyl substituent(s) at the C5-C6 double bond of the uracils. The more the methyl groups at the C5-C6 double bond, the higher the efficiency. The regioselectivity (3/4) ranges from ca. 20 : 80 for 1,3,6-trimethyluracil (1C) to ca. 80 : 20 for 1,3,6-trimethylthymine (1D). The substituent effects would derive from the hyperconjugation of the methyl group(s) at C5 or/and C6 of the uracils, which influences the stability of intermediary triplet 1,4-biradicals and the nucleophilicity of C5 and C6 sites of the double bond. Computational studies reveal that potential energies of triplet 1,4-biradicals forming oxetanes 3, BR5, are 1-4 kcal mol(-1) higher than those of 1,4-biradicals forming oxetanes 4, BR6, and electron densities at C5 are 0.1-0.3 unit higher than those at C6, of the double bond of the uracils, i.e. BR5 are less stable than BR6, and BR5 form more easily than BR6. Temperature effects on the regioselectivity of the Paternò-Büchi reaction of 1D with three benzophenones (2a-c) reveal that efficiencies of oxetanes 3 are higher at a lower reaction temperature, and efficiencies of 4 are higher at a higher temperature. Therefore, triplet biradicals BR5 and BR6 would be regarded as intermediates of kinetic control and thermodynamic control, respectively.