RESUMEN
Through regulation of the epigenome, the bromodomain and extra terminal (BET) family of proteins represent important therapeutic targets for the treatment of human disease. Through mimicking the endogenous N-acetyl-lysine group and disrupting the protein-protein interaction between histone tails and the bromodomain, several small molecule pan-BET inhibitors have progressed to oncology clinical trials. This work describes the medicinal chemistry strategy and execution to deliver an orally bioavailable tetrahydroquinoline (THQ) pan-BET candidate. Critical to the success of this endeavor was a potency agnostic analysis of a data set of 1999 THQ BET inhibitors within the GSK collection which enabled identification of appropriate lipophilicity space to deliver compounds with a higher probability of desired oral candidate quality properties. SAR knowledge was leveraged via Free-Wilson analysis within this design space to identify a small group of targets which ultimately delivered I-BET567 (27), a pan-BET candidate inhibitor that demonstrated efficacy in mouse models of oncology and inflammation.
Asunto(s)
Aminoquinolinas/química , Diseño de Fármacos , Proteínas/metabolismo , Administración Oral , Aminoquinolinas/metabolismo , Aminoquinolinas/farmacocinética , Aminoquinolinas/uso terapéutico , Animales , Benzoatos/química , Benzoatos/metabolismo , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Perros , Semivida , Humanos , Masculino , Ratones , Conformación Molecular , Simulación de Dinámica Molecular , Neoplasias/tratamiento farmacológico , Proteínas/antagonistas & inhibidores , Ratas , Relación Estructura-ActividadRESUMEN
A quinazoline that decreases polyglutamine aggregate burden in a cell-based assay was identified from a high-throughput screen of a chemical-compound library, provided by the NIH Molecular Libraries Small Molecule Repository (MLSMR). A structure and activity study yielded leads with submicromolar potency.
Asunto(s)
Química Farmacéutica/métodos , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas Nucleares/antagonistas & inhibidores , Quinazolinas/química , Técnicas Químicas Combinatorias , Diseño de Fármacos , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Humanos , Proteína Huntingtina , Concentración 50 Inhibidora , Modelos Químicos , Estructura Molecular , Péptidos/química , Relación Estructura-ActividadRESUMEN
Soluble epoxide hydrolase (sEH) is a novel target for the treatment of hypertension and vascular inflammation. A new class of potent non-urea sEH inhibitors was identified via high throughput screening (HTS) and chemical modification. IC(50)s of the most potent compounds range from micromolar to low nanomolar.
Asunto(s)
Descubrimiento de Drogas/métodos , Epóxido Hidrolasas/antagonistas & inhibidores , Epóxido Hidrolasas/metabolismo , Urea/metabolismo , Humanos , Solubilidad , Relación Estructura-Actividad , Urea/química , Urea/clasificación , Urea/farmacologíaRESUMEN
An IKKbeta inhibitor reported to block NF-kappaB transcriptional activities in Jurkat T cells, was found to enhance NF-kappaB translocation in HUVEC cells. These studies suggested a noncanonical NF-kappaB signaling pathway independent of IKKbeta in HUVEC cells.
Asunto(s)
FN-kappa B/metabolismo , Quinazolinas/síntesis química , Quinazolinas/farmacología , Técnicas Químicas Combinatorias , Humanos , Células Jurkat , Leupeptinas/química , Leupeptinas/farmacología , Estructura Molecular , FN-kappa B/efectos de los fármacos , Nitrilos/química , Nitrilos/farmacología , Quinazolinas/química , Sulfonas/química , Sulfonas/farmacología , Sulfóxidos/química , Sulfóxidos/farmacología , Tetrazoles/química , Tetrazoles/farmacologíaRESUMEN
Design, synthesis and biological evaluation of a series of 5-chloropyridine ester-derived severe acute respiratory syndrome-coronavirus chymotrypsin-like protease inhibitors is described. Position of the carboxylate functionality is critical to potency. Inhibitor 10 with a 5-chloropyridinyl ester at position 4 of the indole ring is the most potent inhibitor with a SARS-CoV 3CLpro IC(50) value of 30 nM and an antiviral EC(50) value of 6.9 microM. Molecular docking studies have provided possible binding modes of these inhibitors.
Asunto(s)
Antivirales/síntesis química , Química Farmacéutica/métodos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/metabolismo , Proteínas Virales/antagonistas & inhibidores , Animales , Antivirales/química , Antivirales/farmacología , Dominio Catalítico , Proteasas 3C de Coronavirus , Cisteína Endopeptidasas/química , Diseño de Fármacos , Ésteres , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Unión ProteicaRESUMEN
We report here a class of thiazolidine-2,4-diones and 2-thioxothiazolidin-4-ones as potent inhibitors of the lymphoid specific tyrosine phosphatase (Lyp) identified from high throughput screens. Chemical modification by incorporating the known phosphotyrosine (pTyr) mimics led to the discovery of a salicylate-based inhibitor with submicromolar potency.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 22/antagonistas & inhibidores , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Tiazolidinedionas/farmacología , Tiazolidinas/farmacología , Sitios de Unión , Inhibidores Enzimáticos/síntesis química , Modelos Químicos , Imitación Molecular , Fosfotirosina/química , Relación Estructura-Actividad , Tiazolidinedionas/síntesis química , Tiazolidinas/síntesis químicaRESUMEN
We describe here a series of N-(quinolin-8-yl)benzenesulfonamides capable of suppressing the NFkappaB pathway identified from two high-throughput screens run at two centers of the NIH Molecular Libraries Initiative. These small molecules were confirmed in both primary and secondary assays of NFkappaB activation and expanded upon through analogue synthesis. The series exhibited potencies in the cell-based assays at as low as 0.6 microM, and several indications suggest that the targeted activity lies within a common region of the NFkappaB pathway.
Asunto(s)
FN-kappa B/antagonistas & inhibidores , Quinolinas/farmacología , Sulfonamidas/farmacología , Técnicas Químicas Combinatorias , Regulación hacia Abajo/efectos de los fármacos , FN-kappa B/metabolismo , Quinolinas/química , Relación Estructura-Actividad , Sulfonamidas/química , BencenosulfonamidasRESUMEN
[structure: see text] An enantioselective total synthesis of (-)-lasonolide A is described. The upper tetrahydropyran ring was constructed stereoselectively by an intramolecular 1,3-dipolar cycloaddition reaction. The bicyclic isooxazoline led to the tetrahydropyran ring as well as the quaternary stereocenter present in the molecule. The lower tetrahydropyran ring was assembled by a catalytic asymmetric hetero-Diels-Alder reaction as the key step. Three stereocenters were enantioselectively installed in this single step reaction.
Asunto(s)
Antineoplásicos/síntesis química , Macrólidos/síntesis química , Antineoplásicos/química , Macrólidos/química , Estructura Molecular , Oximas/química , EstereoisomerismoRESUMEN
The lymphoid tyrosine phosphatase (Lyp, PTPN22) is a critical negative regulator of T cell antigen receptor (TCR) signaling. A single-nucleotide polymorphism (SNP) in the ptpn22 gene correlates with the incidence of various autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Since the disease-associated allele is a more potent inhibitor of TCR signaling, specific Lyp inhibitors may become valuable in treating autoimmunity. Using a structure-based approach, we synthesized a library of 34 compounds that inhibited Lyp with IC(50) values between 0.27 and 6.2 µM. A reporter assay was employed to screen for compounds that enhanced TCR signaling in cells, and several inhibitors displayed a dose-dependent, activating effect. Subsequent probing for Lyp's direct physiological targets by immunoblot analysis confirmed the ability of the compounds to inhibit Lyp in T cells. Selectivity profiling against closely related tyrosine phosphatases and in silico docking studies with the crystal structure of Lyp yielded valuable information for the design of Lyp-specific compounds.
Asunto(s)
Benzofuranos/síntesis química , Proteína Tirosina Fosfatasa no Receptora Tipo 22/antagonistas & inhibidores , Salicilatos/síntesis química , Benzofuranos/química , Benzofuranos/farmacología , Humanos , Células Jurkat , Modelos Moleculares , Factores de Transcripción NFATC/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 22/química , Proteína Tirosina Fosfatasa no Receptora Tipo 22/genética , Receptores de Antígenos de Linfocitos T/fisiología , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Salicilatos/química , Salicilatos/farmacología , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Factor de Transcripción AP-1/metabolismoRESUMEN
Many proteins have been proposed to act as surrogate markers of organ damage, yet for many candidates the essential biomarker characteristics that link the protein to the injured organ have not yet been described. We generated an Ngal reporter mouse by inserting a double-fusion reporter gene encoding luciferase-2 and mCherry (Luc2-mC) into the Ngal (Lcn2) locus. The Ngal-Luc2-mC reporter accurately recapitulated the endogenous message and illuminated injuries in vivo in real time. In the kidney, Ngal-Luc2-mC imaging showed a sensitive, rapid, dose-dependent, reversible, and organ- and cell-specific relationship with tubular stress, which correlated with the level of urinary Ngal (uNgal). Unexpectedly, specific cells of the distal nephron were the source of uNgal. Cells isolated from Ngal-Luc2-mC mice also revealed both the onset and the resolution of the injury, and the actions of NF-κB inhibitors and antibiotics during infection. Thus, imaging of Ngal-Luc2-mC mice and cells identified injurious and reparative agents that affect kidney damage.
Asunto(s)
Proteínas de Fase Aguda/fisiología , Genes Reporteros/fisiología , Riñón/lesiones , Lipocalinas/fisiología , Proteínas Oncogénicas/fisiología , Proteínas de Fase Aguda/genética , Animales , Biomarcadores/sangre , Cisplatino/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/fisiología , Genes Reporteros/efectos de los fármacos , Gentamicinas/farmacología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Lípido A/farmacología , Lipocalina 2 , Lipocalinas/sangre , Lipocalinas/genética , Masculino , Ratones , Ratones Mutantes/genética , Ratones Mutantes/fisiología , Proteínas Oncogénicas/sangre , Proteínas Oncogénicas/genéticaRESUMEN
Nuclear factor kappa B (NF-kappaB) is an important transcription factor. Aberrant regulation of the NF-kappaB pathway is frequently observed in a number of major ailments such as cancer and inflammatory diseases. Hence NF-kappaB modulators have been intensely pursued for their potential therapeutic applications. Numerous reviews have described recent progress in the development of these agents. More recently, a variety of structurally and functionally novel small molecules, identified through high-throughput screens conducted within the Molecular Libraries Screening Center Network (MLSCN) of the NIH Roadmap for Medical Research, have been added to the current list of NF-kappaB regulators. This review will discuss the inhibitors and activators newly discovered by Columbia's Molecular Libraries Screening Center (MLSC) using a well-designed and stable cellular assay.
Asunto(s)
Antiinflamatorios/farmacología , Antineoplásicos/farmacología , Bioensayo/métodos , Evaluación Preclínica de Medicamentos/métodos , FN-kappa B/antagonistas & inhibidores , Animales , Antiinflamatorios/química , Antineoplásicos/química , Humanos , Peso Molecular , FN-kappa B/metabolismoRESUMEN
A detailed account of the enantioselective total synthesis of (-)-lasonolide A is described. Our initial synthetic route to the top tetrahydropyran ring involved Evans asymmetric alkylation as the key step. Initially, we relied on the diastereoselective alkylation of an alpha-alkoxyacetimide derivative containing an alpha' stereogenic center and investigated such an asymmetric alkylation reaction. Although alkylation proceeded in good yield, the lack of diastereoselectivity prompted us to explore alternative routes. Our subsequent successful synthetic strategies involved highly diastereoselective cycloaddition routes to both tetrahydropyran rings of lasonolide A. The top tetrahydropyran ring was constructed stereoselectively by an intramolecular 1,3-dipolar cycloaddition reaction. The overall process constructed a bicyclic isoxazoline, which was later unravelled to a functionalized tetrahydropyran ring as well as a quaternary stereocenter present in the molecule. The lower tetrahydropyran ring was assembled by a Jacobsen catalytic asymmetric hetero-Diels-Alder reaction as the key step. The synthesis also features a Lewis acid catalyzed epoxide opening to form a substituted ether stereoselectively.
Asunto(s)
Antineoplásicos/síntesis química , Macrólidos/síntesis química , Antineoplásicos/química , Macrólidos/química , Estructura Molecular , Piranos/química , EstereoisomerismoRESUMEN
An enantioselective first total synthesis and structural revision of the cytotoxic natural product amphidinolide W is described. We initially investigated a ring-closing metathesis based synthetic strategy to form the 12-membered macrocycle. This strategy was unsuccessful as it led to formation of a 17-membered macrocycle. Subsequently, we explored an alternative strategy that involved cross-metathesis followed by a Yamaguchi macrolactonization reaction sequence utilizing the same key intermediates. This strategy led to the synthesis of amphidinolide W. The synthesis was carried out in a convergent manner, and four of the five stereogenic centers in amphidinolide W were set by asymmetric synthesis. The synthesis features Sharpless asymmetric dihydroxylation, diastereoselective alkylation, efficient cross-metathesis of functionalized substrates, and novel functional group transformations using selective lipase-catalyzed hydrolysis of the primary acetate group. Of particular note, the C6 absolute stereochemistry of amphidinolide W has now been revised through our synthesis.
Asunto(s)
Macrólidos/síntesis química , Butiratos/química , Lactonas/química , Macrólidos/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Nitrocompuestos/química , EstereoisomerismoRESUMEN
An enantioselective first total syntheis of amphidinolide W (2) and a revision of its C6 absolute stereochemistry (1) are described. Amphidinolide W (1), a 12-membered macrolide isolated from Amphidinium sp., has shown potent antitumor properties against a variety of NCI tumor cell lines. The synthesis is convergent, and four of the five chiral centers were derived through asymmetric synthesis. The synthesis features Sharpless asymmetric dihydroxylation, diastereoselective alkylation, efficient cross metathesis of functionalized substrates, and novel functional group transformations using selective lipase-catalyzed hydrolysis of the primary acetate group. Of particular note, the C6 absolute stereochemistry of amphidinolide W (1) has now been revised through our current synthesis.