RESUMEN
Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural ligands with optimized properties for systemic intravenous (iv) administration. Our studies have shown that STING activation by 15a leads to an acute innate immune response as measured by cytokine secretion and adaptive immune response via activation of CD8+ cytotoxic T-cells, which ultimately provides robust antitumor efficacy.
Asunto(s)
Proteínas de la Membrana/agonistas , Nucleótidos Cíclicos/química , Pirimidinas/química , Administración Intravenosa , Animales , Sitios de Unión , Línea Celular Tumoral , Semivida , Humanos , Inmunoterapia , Proteínas de la Membrana/metabolismo , Ratones , Simulación del Acoplamiento Molecular , Neoplasias/patología , Neoplasias/terapia , Nucleótidos Cíclicos/metabolismo , Nucleótidos Cíclicos/uso terapéutico , Fosfatos/química , Ratas , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
SUMOylation is a reversible post-translational modification that regulates protein function through covalent attachment of small ubiquitin-like modifier (SUMO) proteins. The process of SUMOylating proteins involves an enzymatic cascade, the first step of which entails the activation of a SUMO protein through an ATP-dependent process catalyzed by SUMO-activating enzyme (SAE). Here, we describe the identification of TAK-981, a mechanism-based inhibitor of SAE which forms a SUMO-TAK-981 adduct as the inhibitory species within the enzyme catalytic site. Optimization of selectivity against related enzymes as well as enhancement of mean residence time of the adduct were critical to the identification of compounds with potent cellular pathway inhibition and ultimately a prolonged pharmacodynamic effect and efficacy in preclinical tumor models, culminating in the identification of the clinical molecule TAK-981.
Asunto(s)
Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Neoplasias/tratamiento farmacológico , Ácidos Sulfónicos/uso terapéutico , Sumoilación/efectos de los fármacos , Enzimas Activadoras de Ubiquitina/antagonistas & inhibidores , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Línea Celular Tumoral , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Humanos , Ratones , Estructura Molecular , Unión Proteica , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Relación Estructura-Actividad , Ácidos Sulfónicos/síntesis química , Ácidos Sulfónicos/metabolismo , Enzimas Activadoras de Ubiquitina/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The ubiquitin-proteasome system (UPS) comprises a network of enzymes that is responsible for maintaining cellular protein homeostasis. The therapeutic potential of this pathway has been validated by the clinical successes of a number of UPS modulators, including proteasome inhibitors and immunomodulatory imide drugs (IMiDs). Here we identified TAK-243 (formerly known as MLN7243) as a potent, mechanism-based small-molecule inhibitor of the ubiquitin activating enzyme (UAE), the primary mammalian E1 enzyme that regulates the ubiquitin conjugation cascade. TAK-243 treatment caused depletion of cellular ubiquitin conjugates, resulting in disruption of signaling events, induction of proteotoxic stress, and impairment of cell cycle progression and DNA damage repair pathways. TAK-243 treatment caused death of cancer cells and, in primary human xenograft studies, demonstrated antitumor activity at tolerated doses. Due to its specificity and potency, TAK-243 allows for interrogation of ubiquitin biology and for assessment of UAE inhibition as a new approach for cancer treatment.
Asunto(s)
Neoplasias/tratamiento farmacológico , Nucleósidos/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Sulfonamidas/farmacología , Enzimas Activadoras de Ubiquitina/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Humanos , Imidas/farmacología , Ratones , Neoplasias/genética , Neoplasias/patología , Complejo de la Endopetidasa Proteasomal/química , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/genética , Unión Proteica , Pirazoles , Pirimidinas , Sulfuros , Ubiquitina/antagonistas & inhibidores , Ubiquitina/química , Ubiquitina/genética , Enzimas Activadoras de Ubiquitina/química , Enzimas Activadoras de Ubiquitina/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Investigations of a biaryl ether scaffold identified tetrahydronaphthalene Raf inhibitors with good in vivo activity; however these compounds had affinity toward the hERG potassium channel. Herein we describe our work to eliminate this hERG activity via alteration of the substituents on the benzoic amide functionality. The resulting compounds have improved selectivity against the hERG channel, good pharmacokinetic properties and potently inhibit the Raf pathway in vivo.
Asunto(s)
Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Tetrahidronaftalenos/química , Animales , Línea Celular Tumoral , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Mutagénesis , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tetrahidronaftalenos/farmacocinética , Tetrahidronaftalenos/uso terapéutico , Trasplante HeterólogoRESUMEN
Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.
Asunto(s)
Antineoplásicos/síntesis química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Tetrahidronaftalenos/síntesis química , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Disponibilidad Biológica , Cristalografía por Rayos X , Diseño de Fármacos , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/enzimología , Melanoma Experimental/patología , Ratones , Ratones Desnudos , Modelos Moleculares , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Estereoisomerismo , Relación Estructura-Actividad , Tetrahidronaftalenos/química , Tetrahidronaftalenos/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The discovery of novel pyrazoline derivatives as B-Raf (V600E) inhibitors is described in this report. Chemical modification of the pyrazoline scaffold led to the development of SAR and identified potent and selective inhibitors of B-Raf (V600E). Determination of the pharmacokinetic properties of selected inhibitors is also reported.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Pirazoles/química , Sustitución de Aminoácidos , Sitios de Unión , Simulación por Computador , Evaluación Preclínica de Medicamentos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Pirazoles/síntesis química , Pirazoles/farmacocinética , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
To improve the pharmacokinetics of a previously reported series of dipeptidyl nitrile cathepsin B inhibitors, the P(2)-P(3) amide group was replaced with an arylamine. Further optimization of this template resulted in highly potent and selective inhibitors with excellent oral availability.