RESUMEN
Through an internal virtual screen at GlaxoSmithKline a distinct class of 2-phenylimidazo[1,2-a]pyridine-6-carboxamide H-PGDS inhibitors were discovered. Careful evaluation of crystal structures and SAR led to a novel, potent, and orally active imidazopyridine inhibitor of H-PGDS, 20b. Herein, describes the identification of 2 classes of inhibitors, their syntheses, and their challenges.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Oxidorreductasas Intramoleculares/metabolismo , Estructura Molecular , Relación Estructura-ActividadRESUMEN
With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50â¯=â¯220,000â¯nM, LEâ¯=â¯0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50â¯=â¯3,100â¯nM, LEâ¯=â¯0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50â¯=â¯9.9â¯nM, LEâ¯=â¯0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Lipocalinas/antagonistas & inhibidores , Quinolinas/química , Quinolinas/farmacología , Animales , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacocinética , Humanos , Oxidorreductasas Intramoleculares/química , Oxidorreductasas Intramoleculares/metabolismo , Lipocalinas/química , Lipocalinas/metabolismo , Masculino , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Quinolinas/farmacocinéticaRESUMEN
IL-17-producing CD4(+)Th17 cells, CD8(+)Tc17 cells, and γδ T cells play critical roles in the pathogenesis of autoimmune psoriasis. RORγt is required for the differentiation of Th17 cells and expression of IL-17. In this article, we describe a novel, potent, and selective RORγt inverse agonist (TMP778), and its inactive diastereomer (TMP776). This chemistry, for the first time to our knowledge, provides a unique and powerful set of tools to probe RORγt-dependent functions. TMP778, but not TMP776, blocked human Th17 and Tc17 cell differentiation and also acutely modulated IL-17A production and inflammatory Th17-signature gene expression (Il17a, Il17f, Il22, Il26, Ccr6, and Il23) in mature human Th17 effector/memory T cells. In addition, TMP778, but not TMP776, inhibited IL-17A production in both human and mouse γδ T cells. IL-23-induced IL-17A production was also blocked by TMP778 treatment. In vivo targeting of RORγt in mice via TMP778 administration reduced imiquimod-induced psoriasis-like cutaneous inflammation. Further, TMP778 selectively regulated Th17-signature gene expression in mononuclear cells isolated from both the blood and affected skin of psoriasis patients. In summary, to our knowledge, we are the first to demonstrate that RORγt inverse agonists: 1) inhibit Tc17 cell differentiation, as well as IL-17 production by γδ T cells and CD8(+) Tc17 cells; 2) block imiquimod-induced cutaneous inflammation; 3) inhibit Th17 signature gene expression by cells isolated from psoriatic patient samples; and 4) block IL-23-induced IL-17A expression. Thus, RORγt is a tractable drug target for the treatment of cutaneous inflammatory disorders, which may afford additional therapeutic benefit over existing modalities that target only IL-17A.
Asunto(s)
Dermatitis/prevención & control , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Células Th17/efectos de los fármacos , Transcriptoma/efectos de los fármacos , Adulto , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Células Cultivadas , Dermatitis/inmunología , Dermatitis/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Transferencia Resonante de Energía de Fluorescencia , Células HEK293 , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Interleucina-17/genética , Interleucina-17/inmunología , Interleucina-17/metabolismo , Células Jurkat , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Psoriasis/sangre , Psoriasis/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Piel/inmunología , Piel/metabolismo , Piel/patología , Bibliotecas de Moléculas Pequeñas/química , Células Th17/inmunología , Células Th17/metabolismo , Transcriptoma/inmunologíaRESUMEN
A novel series of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as RORγt inverse agonists was discovered. Binding mode analysis of a RORγt partial agonist (2c) revealed by co-crystal structure in RORγt LBD suggests that the inverse agonists do not directly interfere with the interaction between H12 and the RORγt LBD. Detailed SAR exploration led to identification of potent RORγt inverse agonists such as 3m with a pIC50 of 8.0. Selected compounds in the series showed reasonable activity in Th17 cell differentiation assay as well as low intrinsic clearance in mouse liver microsomes.
Asunto(s)
Amidas/química , Amidas/farmacología , Agonismo Inverso de Drogas , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Células Th17/efectos de los fármacos , Tiazoles/química , Tiazoles/farmacología , Animales , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Humanos , Ratones , Simulación del Acoplamiento Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Células Th17/citologíaRESUMEN
Novel series of N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides were discovered as potent retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitors. SAR studies of the RORγt HTS hit 6a led to identification of thiazole ketone amide 8h and thiophene ketone amide 9g with high binding affinity and inhibitory activity of Th17 cell differentiation. Compound 8h showed in vivo efficacy in both mouse experimental autoimmune encephalomyelitis (EAE) and collagen induced arthritis (CIA) models via oral administration.
Asunto(s)
Amidas/farmacología , Artritis/tratamiento farmacológico , Descubrimiento de Drogas , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Administración Oral , Amidas/administración & dosificación , Amidas/química , Animales , Artritis/inducido químicamente , Diferenciación Celular/efectos de los fármacos , Colágeno , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Estructura Molecular , Relación Estructura-Actividad , Células Th17RESUMEN
A series of estrogen receptor ligands based on a 3-alkyl naphthalene scaffold was synthesized using an intramolecular enolate-alkyne cycloaromatization as the key step. Several of these compounds bearing a C6-OH group were shown to be high affinity ligands. All compounds had similar ERalpha and ERbeta binding affinity ranging from micromolar to low nanomolar.
Asunto(s)
Naftalenos/síntesis química , Naftalenos/farmacología , Receptores de Estrógenos/agonistas , Técnicas Químicas Combinatorias , Moduladores de los Receptores de Estrógeno/metabolismo , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Femenino , Humanos , Ligandos , Estructura Molecular , Naftalenos/química , Moduladores Selectivos de los Receptores de Estrógeno/metabolismo , Relación Estructura-ActividadRESUMEN
Biaryl amides as new RORγt modulators were discovered. The crystal structure of biaryl amide agonist 6 in complex with RORγt ligand binding domain (LBD) was resolved, and both "short" and "long" inverse agonists were obtained by removing from 6 or adding to 6 a proper structural moiety. While "short" inverse agonist (8) recruits a corepressor peptide and dispels a coactivator peptide, "long" inverse agonist (9) dispels both. The two types of inverse agonists can be utilized as potential tools to study mechanisms of Th17 transcriptional network inhibition and related disease biology.
RESUMEN
The estrogen-related receptor alpha (ERRalpha) is a potential target for activation in the treatment of metabolic disease. To date, no small-molecule agonists of ERRalpha have been identified despite several high-throughput screening campaigns. We describe the synthesis and profiling of a small array of compounds designed on the basis of a previously reported agonist-bound crystal structure of the closely related receptor ERRgamma. The results suggest that ERRalpha may be intractable as a direct target for pharmacologic activation.
Asunto(s)
Hidrazonas/química , Hidrazonas/farmacología , Receptores de Estrógenos/agonistas , Receptores de Estrógenos/química , Sitios de Unión , Cristalografía por Rayos X , Agonismo Inverso de Drogas , Transferencia Resonante de Energía de Fluorescencia , Células HeLa , Humanos , Hidrazonas/síntesis química , Receptores de Estrógenos/antagonistas & inhibidores , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
The first small molecule agonists of the estrogen-related receptors have been identified. GSK4716 (3) and GSK9089 (4) show binding to ERRgamma with remarkable selectivity over the classical estrogen receptors. Notably, in cell-based reporter assays, 3 mimics the protein ligand PGC-1alpha in activation of human ERRbeta and ERRgamma.
Asunto(s)
Receptor beta de Estrógeno/agonistas , Hidrazinas/síntesis química , Fenoles/síntesis química , Receptores de Estrógenos/agonistas , Unión Competitiva , Receptor beta de Estrógeno/genética , Transferencia Resonante de Energía de Fluorescencia , Genes Reporteros , Células HeLa , Proteínas de Choque Térmico/biosíntesis , Humanos , Hidrazinas/química , Hidrazinas/farmacología , Ligandos , Imitación Molecular , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Fenoles/química , Fenoles/farmacología , Receptores de Estrógenos/genética , Relación Estructura-Actividad , Factores de Transcripción/biosíntesisRESUMEN
A series of 1,3,5-triazine-based estrogen receptor (ER) modulators that are modestly selective for the ERbeta subtype are reported. Compound 1, which displayed modest potency and selectivity for ERbeta vs ERalpha, was identified via high-throughput screening utilizing an ERbeta SPA-based binding assay. Subsequent analogue preparation resulted in the identification of compounds such as 21 and 43 that display 25- to 30-fold selectivity for ERbeta with potencies in the 10-30 nM range. These compounds profile as full antagonists at ERbeta and weak partial agonists at ERalpha in a cell-based reporter gene assay. In addition, the X-ray crystal structure of compound 15 complexed with the ligand binding domain of ERbeta has been solved and was utilized in the design of more conformationally restrained analogues such as 31 in an attempt to increase selectivity for the ERbeta subtype.
Asunto(s)
Receptores de Estrógenos/efectos de los fármacos , Triazinas/síntesis química , Cristalografía por Rayos X , Receptor alfa de Estrógeno , Receptor beta de Estrógeno , Genes Reporteros , Humanos , Ligandos , Modelos Moleculares , Ensayo de Unión Radioligante , Receptores de Estrógenos/agonistas , Receptores de Estrógenos/antagonistas & inhibidores , Receptores de Estrógenos/genética , Estereoisomerismo , Relación Estructura-Actividad , Transcripción Genética , Triazinas/química , Triazinas/farmacología , Células Tumorales CultivadasRESUMEN
A novel series of tertiary amines as retinoid-related orphan receptor gamma-t (RORγt) inverse agonists was discovered through agonist/inverse agonist conversion. The level of RORγt inhibition can be enhanced by modulating the conformational disruption of H12 in RORγt LBD. Linker exploration and rational design led to the discovery of more potent indole-based RORγt inverse agonists.
RESUMEN
BACKGROUND: Most normal cells in the presence of oxygen utilize glucose for mitochondrial oxidative phosphorylation. In contrast, many cancer cells rapidly convert glucose to lactate in the cytosol, a process termed aerobic glycolysis. This glycolytic phenotype is enabled by lactate dehydrogenase (LDH), which catalyzes the inter-conversion of pyruvate and lactate. The purpose of this study was to identify and characterize potent and selective inhibitors of LDHA. METHODS: High throughput screening and lead optimization were used to generate inhibitors of LDHA enzymatic activity. Effects of these inhibitors on metabolism were evaluated using cell-based lactate production, oxygen consumption, and 13C NMR spectroscopy assays. Changes in comprehensive metabolic profile, cell proliferation, and apoptosis were assessed upon compound treatment. RESULTS: 3-((3-carbamoyl-7-(3,5-dimethylisoxazol-4-yl)-6-methoxyquinolin-4-yl) amino) benzoic acid was identified as an NADH-competitive LDHA inhibitor. Lead optimization yielded molecules with LDHA inhibitory potencies as low as 2 nM and 10 to 80-fold selectivity over LDHB. Molecules in this family rapidly and profoundly inhibited lactate production rates in multiple cancer cell lines including hepatocellular and breast carcinomas. Consistent with selective inhibition of LDHA, the most sensitive breast cancer cell lines to lactate inhibition in hypoxic conditions were cells with low expression of LDHB. Our inhibitors increased rates of oxygen consumption in hepatocellular carcinoma cells at doses up to 3 microM, while higher concentrations directly inhibited mitochondrial function. Analysis of more than 500 metabolites upon LDHA inhibition in Snu398 cells revealed that intracellular concentrations of glycolysis and citric acid cycle intermediates were increased, consistent with enhanced Krebs cycle activity and blockage of cytosolic glycolysis. Treatment with these compounds also potentiated PKM2 activity and promoted apoptosis in Snu398 cells. CONCLUSIONS: Rapid chemical inhibition of LDHA by these quinoline 3-sulfonamids led to profound metabolic alterations and impaired cell survival in carcinoma cells making it a compelling strategy for treating solid tumors that rely on aerobic glycolysis for survival.
RESUMEN
REV-ERBα has emerged as an important target for regulation of circadian rhythm and its associated physiology. Herein, we report on the optimization of a series of REV-ERBα agonists based on GSK4112 (1) for potency, selectivity, and bioavailability. (1) Potent REV-ERBα agonists 4, 10, 16, and 23 are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LXRα. Amine 4 demonstrated in vivo bioavailability after either iv or oral dosing.
Asunto(s)
Aminas/síntesis química , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/agonistas , Aminas/química , Aminas/farmacología , Animales , Disponibilidad Biológica , Proteínas Portadoras/metabolismo , Línea Celular , Ritmo Circadiano , Glicina/análogos & derivados , Glicina/síntesis química , Glicina/química , Glicina/farmacología , Humanos , Receptores X del Hígado , Ratones , Ratones Endogámicos C57BL , Receptores Nucleares Huérfanos/metabolismo , Fragmentos de Péptidos/metabolismo , Proteínas de Unión al ARN , Ensayo de Unión Radioligante , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/química , Tiofenos/farmacologíaRESUMEN
Optical microplate-based biosensors combine the advantages of label-free detection with industry-standard assay laboratory infrastructure and scalability. A plate-based label-free platform allows the same basic platform to be used to quantify molecular interactions of macromolecules and to screen and characterize drug-like small-molecule interactions. The ligand-binding domain of orphan estrogen-related nuclear receptor-γ (ERRγ) is utilized, as a model system of a challenging type of target, to illustrate the rapid development and utility of a range of biochemical assay formats on these biosensors. Formats in which either the domain, or a peptide derived from its cognate corepressor, RIP140, were immobilized were utilized. The direct binding of small drug molecules to the domain was characterized using immobilized domain. Subsequent addition of peptide distinguished whether compounds acted as either antagonists of peptide binding, or as agonists promoting a ternary complex. The format with peptide immobilized gave a more sensitive procedure for establishing the effect of compounds on the domain-peptide interaction. Using a direct-binding format, a diverse chemical library of 1,408 compounds in DMSO was screened for ability to bind to biosensors coated with ERRγ ligand-binding domain. Hits were then characterized using the other biosensor assay formats. The standard requirements for a full primary screening campaign were fulfilled by the acceptable hit-rate, quality-performance parameters, and throughput of the direct-binding assay format. Such a format allows direct screening of targets, such as orphan receptors, without the requirement for prior knowledge of a validated ligand.
Asunto(s)
Técnicas Biosensibles/métodos , Evaluación Preclínica de Medicamentos/métodos , Fenómenos Ópticos , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Estrógenos/metabolismo , Bibliotecas de Moléculas Pequeñas/análisis , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Biotinilación , Núcleo Celular , Descubrimiento de Drogas , Humanos , Ligandos , Sustancias Macromoleculares , Modelos Teóricos , Terapia Molecular Dirigida , Proteínas Nucleares/metabolismo , Proteína de Interacción con Receptores Nucleares 1 , Péptidos/metabolismo , Unión Proteica , Reproducibilidad de los Resultados , Bibliotecas de Moléculas Pequeñas/metabolismo , EstereoisomerismoRESUMEN
The crystal structure of LRH-1 ligand binding domain bound to our previously reported agonist 3-(E-oct-4-en-4-yl)-1-phenylamino-2-phenyl-cis-bicyclo[3.3.0]oct-2-ene 5 is described. Two new classes of agonists in which the bridgehead anilino group from our first series was replaced with an alkoxy or 1-ethenyl group were designed, synthesized, and tested for activity in a peptide recruitment assay. Both new classes gave very active compounds, particularly against SF-1. Structure-activity studies led to excellent dual-LRH-1/SF-1 agonists (e.g., RJW100) as well as compounds selective for LRH-1 (RJW101) and SF-1 (RJW102 and RJW103). The series based on 1-ethenyl substitution was acid stable, overcoming a significant drawback of our original bridgehead anilino-substituted series. Initial studies on the regulation of gene expression in human cell lines showed excellent, reproducible activity at endogenous target genes.
Asunto(s)
Receptores Citoplasmáticos y Nucleares/agonistas , Bibliotecas de Moléculas Pequeñas/farmacología , Factor Esteroidogénico 1/agonistas , Secuencia de Aminoácidos , Animales , Cristalografía por Rayos X , Células HEK293 , Humanos , Ligandos , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Conformación Proteica , Receptores Citoplasmáticos y Nucleares/química , Receptores Citoplasmáticos y Nucleares/metabolismo , Homología de Secuencia de Aminoácido , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Factor Esteroidogénico 1/química , Factor Esteroidogénico 1/metabolismo , Activación Transcripcional/efectos de los fármacosRESUMEN
The identification of nonporphyrin ligands for the orphan nuclear receptor Rev-erbα will enable studies of its role as a heme sensor and regulator of metabolic and circadian signaling. We describe the development of a biochemical assay measuring the interaction between Rev-erbα and a peptide from the nuclear receptor corepressor-1 (NCoR). The assay was utilized to identify a small molecule ligand for Rev-erbα, GSK4112 (1), that was competitive with heme. In cells, 1 profiled as a Rev-erbα agonist in cells to inhibit expression of the circadian target gene bmal1. In addition, 1 repressed the expression of gluconeogenic genes in liver cells and reduced glucose output in primary hepatocytes. Therefore, 1 is useful as a chemical tool to probe the function of Rev-erbα in transcriptional repression, regulation of circadian biology, and metabolic pathways. Additionally, 1 may serve as a starting point for design of Rev-erbα chemical probes with in vivo pharmacological activity.
Asunto(s)
Glicina/análogos & derivados , Co-Represor 1 de Receptor Nuclear/metabolismo , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/metabolismo , Péptidos/metabolismo , Mapeo de Interacción de Proteínas/métodos , Bibliotecas de Moléculas Pequeñas/metabolismo , Tiofenos/metabolismo , Secuencia de Aminoácidos , Animales , Unión Competitiva , Línea Celular , Células Cultivadas , Ritmo Circadiano , Glicina/química , Glicina/metabolismo , Hemo/metabolismo , Hepatocitos/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Co-Represor 1 de Receptor Nuclear/química , Péptidos/química , Bibliotecas de Moléculas Pequeñas/química , Tiofenos/químicaRESUMEN
X-ray crystal structures of the ligand binding domain (LBD) of the estrogen-related receptor-gamma (ERRgamma) were determined that describe this receptor in three distinct states: unliganded, inverse agonist bound, and agonist bound. Two structures were solved for the unliganded state, the ERRgamma LBD alone, and in complex with a coregulator peptide representing a portion of receptor interacting protein 140 (RIP140). No significant differences were seen between these structures that both exhibited the conformation of ERRgamma seen in studies with other coactivators. Two structures were obtained describing the inverse agonist-bound state, the ERRgamma LBD with 4-hydroxytamoxifen (4-OHT), and the ERRgamma LBD with 4-OHT and a peptide representing a portion of the silencing mediator of retinoid and thyroid hormone action protein (SMRT). The 4-OHT structure was similar to other reported inverse agonist bound structures, showing reorientation of phenylalanine 435 and a displacement of the AF-2 helix relative to the unliganded structures with little other rearrangement occurring. No significant changes to the LBD appear to be induced by peptide binding with the addition of the SMRT peptide to the ERRgamma plus 4-OHT complex. The observed agonist-bound state contains the ERRgamma LBD, a ligand (GSK4716), and the RIP140 peptide and reveals an unexpected rearrangement of the phenol-binding residues. Thermal stability studies show that agonist binding leads to global stabilization of the ligand binding domain. In contrast to the conventional mechanism of nuclear receptor ligand activation, activation of ERRgamma by GSK4716 does not appear to involve a major rearrangement or significant stabilization of the C-terminal helix.
Asunto(s)
Receptores Citoplasmáticos y Nucleares/química , Receptores de Estrógenos/química , Sitios de Unión , Dicroismo Circular , Cristalografía por Rayos X , Humanos , Técnicas In Vitro , Ligandos , Modelos Moleculares , Complejos Multiproteicos , Estructura Cuaternaria de Proteína , Estructura Terciaria de Proteína , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Estrógenos/agonistas , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Electricidad EstáticaRESUMEN
The design and synthesis of 4-hydroxytamoxifen (4-OHT) derivatives are described. The binding affinities of these compounds toward the orphan estrogen-related receptor gamma and the classical estrogen receptor alpha demonstrate that analogs bearing hydroxyalkyl groups display improved binding selectivity profiles compared with that of 4-OHT. An X-ray crystal structure of one of the designed compounds bound to ERRgamma LBD confirms the molecular basis of the selectivity.