RESUMEN
Synthesis of medium-sized rings is known to be challenging due to high transannular strain especially for 9- and 10-membered rings. Herein we report design and synthesis of unprecedented 9- and 10-membered purine 8,5'-cyclonucleosides as the first cyclonucleoside PRMT5 inhibitors. The cocrystal structure of PRMT5:MEP50 in complex with the synthesized 9-membered cyclonucleoside 1 revealed its binding mode in the SAM binding pocket of PRMT5.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Proteína-Arginina N-Metiltransferasas , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteína-Arginina N-Metiltransferasas/químicaRESUMEN
Mutant isocitrate dehydrogenase 1 (IDH1) has been identified as an attractive oncology target for which >70% of grade II and III gliomas and â¼10% of acute myeloid leukemia (AML) harbor somatic IDH1 mutations. These mutations confer a neomorphic gain of function, leading to the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). We identified and developed a potent, selective, and orally bioavailable brain-penetrant tricyclic diazepine scaffold that inhibits mutant IDH1. During the course of in vitro metabolism studies, GSH-adduct metabolites were observed. The hypothesis for GSH-adduct formation was driven by the electron-rich nature of the tricyclic core. Herein, we describe our efforts to reduce the electron-rich nature of the core. Ultimately, a strategy focused on core modifications to block metabolic hot spots coupled with substitution pattern changes (C8 N â C linked) led to the identification of new tricyclic analogues with minimal GSH-adduct formation across species while maintaining an overall balanced profile.
RESUMEN
We present an automated NMR-guided docking workflow that can be used to generate models of protein-ligand complexes based on data from NOE NMR experiments. The first step is to generate a number of intermolecular distance constraints from experimental NOE data. Then, the ligand is docked on an ensemble of receptor structures to account for protein flexibility, and multiple poses are generated. Finally, we use the NOE-based constraints to filter and score docking poses based on the percentage of NOE constraints that are consistent with protein-ligand interatomic distances. This workflow was successfully used during a lead optimization project to generate models of synthetic protein-protein interaction (PPI) inhibitors bound to the HDM2 protein.
Asunto(s)
Proteínas , Sitios de Unión , Ligandos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Unión Proteica , Conformación Proteica , Proteínas/químicaRESUMEN
Identification of low-dose, low-molecular-weight, drug-like inhibitors of protein-protein interactions (PPIs) is a challenging area of research. Despite the challenges, the therapeutic potential of PPI inhibition has driven significant efforts toward this goal. Adding to recent success in this area, we describe herein our efforts to optimize a novel purine carboxylic acid-derived inhibitor of the HDM2-p53 PPI into a series of low-projected dose inhibitors with overall favorable pharmacokinetic and physical properties. Ultimately, a strategy focused on leveraging known binding hot spots coupled with biostructural information to guide the design of conformationally constrained analogs and a focus on efficiency metrics led to the discovery of MK-4688 (compound 56), a highly potent, selective, and low-molecular-weight inhibitor suitable for clinical investigation.
Asunto(s)
Imidazoles/química , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Piridinas/química , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Humanos , Unión Proteica , Proteínas Proto-Oncogénicas c-mdm2/química , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the post-translational symmetric dimethylation of protein substrates. PRMT5 plays a critical role in regulating biological processes including transcription, cell cycle progression, RNA splicing, and DNA repair. As such, dysregulation of PRMT5 activity is implicated in the development and progression of multiple cancers and is a target of growing clinical interest. Described herein are the structure-based drug designs, robust synthetic efforts, and lead optimization strategies toward the identification of two novel 5,5-fused bicyclic nucleoside-derived classes of potent and efficacious PRMT5 inhibitors. Utilization of compound docking and strain energy calculations inspired novel designs, and the development of flexible synthetic approaches enabled access to complex chemotypes with five contiguous stereocenters. Additional efforts in balancing bioavailability, solubility, potency, and CYP3A4 inhibition led to the identification of diverse lead compounds with favorable profiles, promising in vivo activity, and low human dose projections.
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Aminoquinolinas/uso terapéutico , Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Neoplasias/tratamiento farmacológico , Nucleósidos/uso terapéutico , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Aminoquinolinas/síntesis química , Aminoquinolinas/metabolismo , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Femenino , Humanos , Ratones SCID , Simulación del Acoplamiento Molecular , Estructura Molecular , Nucleósidos/síntesis química , Nucleósidos/metabolismo , Unión Proteica , Proteína-Arginina N-Metiltransferasas/metabolismo , Relación Estructura-ActividadRESUMEN
Protein arginine methyltransferase 5 (PRMT5) belongs to a family of enzymes that regulate the posttranslational modification of histones and other proteins via methylation of arginine. Methylation of histones is linked to an increase in transcription and regulates a manifold of functions such as signal transduction and transcriptional regulation. PRMT5 has been shown to be upregulated in the tumor environment of several cancer types, and the inhibition of PRMT5 activity was identified as a potential way to reduce tumor growth. Previously, four different modes of PRMT5 inhibition were known-competing (covalently or non-covalently) with the essential cofactor S-adenosyl methionine (SAM), blocking the substrate binding pocket, or blocking both simultaneously. Herein we describe an unprecedented conformation of PRMT5 in which the formation of an allosteric binding pocket abrogates the enzyme's canonical binding site and present the discovery of potent small molecule allosteric PRMT5 inhibitors.
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Structure- and ligand-based virtual-screening methods (docking, 2D- and 3D-similarity searching) were analyzed for their effectiveness in virtual screening against FFAR2. To evaluate the performance of these methods, retrospective virtual screening was performed. Statistical quality of the methods was evaluated by BEDROC and RIE. The results revealed that electrostatic similarity search protocol using EON (ET combo) outperformed all other protocols with outstanding enrichment of >95% in top 1% and 2% of the dataset with an AUC of 0.958. Interestingly, the hit lists that are obtained from different virtual-screening methods are generally highly complementary to hits found from electrostatic similarity searching. These results suggest that considering electrostatic similarity searching first increases the chance of identifying more (and more diverse) active compounds from a virtual-screening campaign. Accordingly, prospective virtual screening using electrostatic similarity searching was used to identify novel FFAR2 ligands. The discovered compounds provide new chemical matter starting points for the initiation of a medicinal chemistry campaign.
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Antiinflamatorios no Esteroideos/farmacología , Receptores de Superficie Celular/agonistas , Antiinflamatorios no Esteroideos/química , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Células HEK293 , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
This study reports the establishment of a bone marrow mononuclear cell (BMMC) 3D culture model and the application of this model to define sensitivity and resistance biomarkers of acute myeloid leukaemia (AML) patient bone marrow samples in response to Cytarabine (Ara-C) treatment. By mimicking physiological bone marrow microenvironment, the growth conditions were optimized by using frozen BMMCs derived from healthy donors. Healthy BMMCs are capable of differentiating into major hematopoietic lineages and various types of stromal cells in this platform. Cryopreserved BMMC samples from 49 AML patients were characterized for ex vivo growth and sensitivity to Ara-C. RNA sequencing was performed for 3D and 2D cultures to determine differential gene expression patterns. Specific genetic mutations and/or gene expression signatures associated with the ability of the ex vivo expansion and response to Ara-C were elucidated by whole-exome and RNA sequencing. Data analysis identified unique gene expression signatures and novel genetic mutations associated with sensitivity to Ara-C treatment of proliferating AML specimens and can be used as predictive therapeutic biomarkers to determine the optimal treatment regimens. Furthermore, these data demonstrate the translational value of this ex vivo platform which should be widely applicable to evaluate other therapies in AML.
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Citarabina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Modelos Biológicos , Adulto , Anciano , Anciano de 80 o más Años , Células de la Médula Ósea/metabolismo , Línea Celular Tumoral , Citarabina/farmacología , Femenino , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Masculino , Persona de Mediana Edad , Mutación/genética , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Resultado del TratamientoRESUMEN
An internal HTS effort identified a novel PDE2 inhibitor series that was subsequently optimized for improved PDE2 activity and off-target selectivity. The optimized lead, compound 4, improved cognitive performance in a rodent novel object recognition task as well as a non-human primate object retrieval task. In addition, co-crystallization studies of close analog of 4 in the PDE2 active site revealed unique binding interactions influencing the high PDE isoform selectivity.
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Ácido Acético/farmacología , Disfunción Cognitiva/tratamiento farmacológico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/antagonistas & inhibidores , Indoles/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Ácido Acético/síntesis química , Ácido Acético/química , Animales , Dominio Catalítico/efectos de los fármacos , Disfunción Cognitiva/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/metabolismo , Relación Dosis-Respuesta a Droga , Indoles/síntesis química , Indoles/química , Estructura Molecular , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/química , Ratas , Relación Estructura-ActividadRESUMEN
IMPORTANCE OF THE FIELD: Lck (p56(lck) or lymphocyte specific kinase) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (NK) cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T cell receptor (TCR)-mediated signaling, leading to normal T-cell development and activation. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. AREAS COVERED IN THIS REVIEW: This review covers the patents, patent applications and associated publications for small molecule kinase inhibitors of Lck since 2005 and attempts to place them in context from a structural point of view. WHAT THE READER WILL GAIN: Readers will gain an overview of the structural classes and binding modes of Lck inhibitors, the major players in this area and an insight into the current state of the field. TAKE HOME MESSAGE: The search for a potent and orally active inhibitor of Lck has been an intense area of research for a number of years. Despite tremendous efforts, the identification of a highly selective and potent Lck inhibitor suitable for use as an immunosuppressive agent remains elusive.
Asunto(s)
Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Linfocitos T/efectos de los fármacos , Animales , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/fisiopatología , Diseño de Fármacos , Rechazo de Injerto/prevención & control , Humanos , Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Ratones , Ratones Noqueados , Trasplante de Órganos/métodos , Patentes como Asunto , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal/efectos de los fármacos , Linfocitos T/metabolismoRESUMEN
Palladium-catalyzed asymmetric allylic alkylation has proven to be a powerful method for the preparation of a wide variety of chiral compounds and the rapid assembly of complex molecular architecture from simple starting materials. While many types of catalyst systems have been successfully employed with certain systems, diphenylphosphino benzoic acid (DPPBA) based ligands have found use over a broad range of substrate classes. This Account highlights the mechanistic aspects considered when designing reactions with DPPBA-based ligands and presents a working model for the a priori prediction of their stereochemical outcome.
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Compuestos Alílicos/química , Benzamidas/química , Paladio/química , Fosfinas/química , Alquilación , Catálisis , Ligandos , Modelos Químicos , Conformación Molecular , EstereoisomerismoRESUMEN
An atom economic, selective, and highly practical two-metal one-pot synthesis of heterocycles has been developed that efficiently affords enantio- and diastereopure N- and O-heterocyclic products. Furthermore, use of a chiral catalyst in the two-metal procedure allows formation of all possible diastereomers, even those that are traditionally difficult to access via cyclization routes due to thermodynamics. Interestingly, the nature of the enantiodiscriminating event differs between the use of amine versus alcohol nucleophiles. The method also affords heterocyclic products that are synthetically useful intermediates. Through the Z-vinylsilane a variety of stereodefined trisubstituted olefin products can be accessed including several all-carbon motifs. Finally, the utility of these heterocyclic products in total synthesis is demonstrated through concise syntheses of a kainoid intermediate, a constituent of oil of rose, and the ring B portion of bryostatin, a potent chemotherapeutic.
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Compuestos Heterocíclicos/síntesis química , Paladio/química , Rutenio/química , Alquinos/química , Brioestatinas , Catálisis , Ciclización , Furanos/síntesis química , Macrólidos/síntesis química , Piperidinas/síntesis química , Piranos/síntesis química , EstereoisomerismoRESUMEN
The ability to use aliphatic alcohols as competent nucleophiles in the palladium-catalyzed dynamic kinetic asymmetric transformation of Baylis-Hillman adducts is explored. High yield and enantioselectivity is obtained for both the kinetic transformation and dynamic kinetic transformation. The absolute stereochemistry of the products is used to explore the reactive conformation of 2-substituted pi-allyl complexes with DPPBA-based chiral ligands. The utility of this method is further demonstrated in the context of a concise total synthesis of the gastrulation inhibitor (+)-hippospongic acid A. The synthesis features three palladium-catalyzed allylic alkylation reactions to introduce three different bond types: C-S, C-H, and C-O.
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Alcoholes/química , Ácidos Carboxílicos/síntesis química , Triterpenos/síntesis química , Alcoholes/síntesis química , Alquilación , Compuestos Alílicos/química , Catálisis , Cinética , Paladio/química , EstereoisomerismoRESUMEN
[reaction: see text] Ruthenium-catalyzed alkyne hydrosilylation or silyl-alkyne Alder ene reactions provide entry into benzyldimethylsilyl (BDMS)-substituted alkenes. The BDMS-vinylsilanes are further elaborated through mild palladium-catalyzed cross coupling and show significant stability to intervening synthetic operations, including silyl ether deprotection.