RESUMEN
[This corrects the article DOI: 10.18632/oncotarget.27589.].
RESUMEN
The androgen receptor (AR) is a major driver of prostate cancer development and progression. Men who develop advanced prostate cancer often have long-term cancer control when treated with androgen-deprivation therapies (ADT). Still, their disease inevitably becomes resistant to ADT and progresses to castration-resistant prostate cancer (CRPC). ADT involves potent competitive AR antagonists and androgen synthesis inhibitors. Resistance to these types of treatments emerges, primarily through the maintenance of AR signaling by ligand-independent activation mechanisms. There is a need to find better ways to block AR to overcome CRPC. In the findings reported here, we demonstrate that the nuclear scaffold protein, nucleolin (NCL), suppresses the expression of AR. NCL binds to a G-rich region in the AR promoter that forms a G-quadruplex (G4) structure. Binding of NCL to this G4-element is required for NCL to suppress AR expression, specifically in AR-expressing tumor cells. Compounds that stabilize G4 structures require NCL to associate with the G4-element of the AR promoter in order to decrease AR expression. A newly discovered G4 compound that suppresses AR expression demonstrates selective killing of AR-expressing tumor cells, including CRPC lines. Our findings raise the significant possibility that G4-stabilizing drugs can be used to increase NCL transcriptional repressor activity to block AR expression in prostate cancer. Our studies contribute to a clearer understanding of the mechanisms that control AR expression, which could be exploited to overcome CRPC.
RESUMEN
This G-rich region of the c-MYC promoter has been shown to form a G-quadruplex structure that acts as a silencer element for c-MYC transcriptional control. In the present work, we have synthesized a series of 11-substituted quindoline analogues as c-MYC G-quadruplex-stabilizing compounds, and the cell-free and in vitro activity of these compounds were evaluated. Two lead compounds (4 and 12) demonstrated good cell-free profiles, and compound 4 (2-(4-(10H-indolo[3,2-b]quinolin-11-yl)piperazin-1-yl)-N,N-dimethylethanamine) significantly down-regulated c-MYC expression. However, despite the good cell-free activity and the effect of these compounds on c-MYC gene expression, we have demonstrated, using a cellular assay in a Burkitt's lymphoma cell line (CA46-specific), that these effects were not mediated through targeting of the c-MYC G-quadruplex. Thus, caution should be used in assigning the effects of G-quadruplex-interactive compounds that lower c-MYC to direct targeting of these promoter elements unless this assay, or similar ones, demonstrates direct targeting of the G-quadruplex in cells.
Asunto(s)
Alcaloides/química , Antineoplásicos/química , Antineoplásicos/farmacología , G-Cuádruplex/efectos de los fármacos , Indoles/química , Indoles/farmacología , Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidores , Quinolinas/química , Quinolinas/farmacología , Antineoplásicos/síntesis química , Regulación de la Expresión Génica/efectos de los fármacos , Células HCT116 , Humanos , Indoles/síntesis química , Concentración 50 Inhibidora , Neoplasias/metabolismo , Regiones Promotoras Genéticas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-myc/genética , Quinolinas/síntesis química , Elementos Silenciadores TranscripcionalesRESUMEN
In the title compound, C(22)H(24)N(4)O, the aromatic moiety is essentially planar (r.m.s. deviation of a least-squares plane fitted through all non-H atoms = 0.0386â Å) and is rotated by 89.98â (4)° from the piperazine ring, which adopts the expected chair conformation. The propanol chain is not fully extended away from the piperazine ring. In the crystal, there are two unique hydrogen-bonding inter-actions. One is an O-Hâ¯N inter-action which, together with an inversion-related symmetry equivalent, forms a ring motif. The second is an N-Hâ¯N inter-action which links adjacent mol-ecules by means of a chain motif which propagates in the c-axis direction. Overall, a two-dimensional hydrogen-bonded structure is formed.
RESUMEN
A new class of bicyclic pyrrolopyrimidine-based Janus kinase 3 (JAK-3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK-3.
Asunto(s)
Janus Quinasa 3/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirroles/síntesis química , Enfermedades Autoinmunes/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Inmunidad/efectos de los fármacos , Janus Quinasa 2/antagonistas & inhibidores , Pirimidinas/farmacología , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
Peptidomimetic compounds possessing a caprolactam ring constraint were prepared and evaluated as interleukin-1beta converting enzyme (ICE) inhibitors. The caprolactam ring was used to constrain the P3 region of our inhibitors. This strategy proved to be effective for the synthesis of ICE inhibitors, maintaining key hydrogen bond interactions with the enzyme and invoking a preferred conformation for binding. Several compounds exhibited IC(50) values less than 10nM in a caspase-1 enzyme assay and less than 100nM in a THP-1 whole cell assay measuring IL-1beta production. Two compounds, 13c and 13j, were found to have good oral bioavailability (>50%) in rats when administered as prodrugs.
Asunto(s)
Caprolactama/síntesis química , Inhibidores de Caspasas , Inhibidores Enzimáticos/farmacología , Serpinas/síntesis química , Proteínas Virales/síntesis química , Animales , Disponibilidad Biológica , Caprolactama/química , Caprolactama/farmacología , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Enlace de Hidrógeno , Interleucina-1beta/metabolismo , Masculino , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Serpinas/farmacología , Relación Estructura-Actividad , Proteínas Virales/farmacologíaRESUMEN
This communication details the synthesis, biological activity, and binding mode of a novel class of 2-benzimidazole substituted pyrimidines. The most potent analogs disclosed showed low nanomolar activity for the inhibition of Lck kinase and a representative analog was co-crystallized with Hck (a structurally related member of the Src family kinases).
Asunto(s)
Bencimidazoles/química , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Enlace de Hidrógeno , Concentración 50 Inhibidora , Interleucina-2/metabolismo , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/síntesis química , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/metabolismo , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-hck/química , Proteínas Proto-Oncogénicas c-hck/metabolismo , Relación Estructura-ActividadRESUMEN
A new class of pyrimidine-based Janus tyrosine kinase 3 (JAK3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK3.
Asunto(s)
Janus Quinasa 3/antagonistas & inhibidores , Pirimidinas/química , Pirimidinas/farmacologíaRESUMEN
An 8,5-fused bicyclic peptidomimetic ring system generated by a stereoselective ring metathesis reaction was elaborated into potent inhibitors of interleukin-1beta converting enzyme (ICE, caspase-1). Multiple compounds were found that exhibited ICE IC50 values < 10 nM and were selective over caspase-3 and caspase-8. These active analogs generally possessed good activity (IC50 values < 100 nM) in a whole cell assay measuring IL-1beta production. Pharmacokinetic analysis of the ethyl acetal prodrug form of a selected active lead revealed a compound with a reasonable plasma half-life (1.1 h) and good oral bioavailability (30%).
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Inhibidores de Caspasas , Péptidos Cíclicos/farmacología , Animales , Disponibilidad Biológica , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Semivida , Concentración 50 Inhibidora , Imitación Molecular , Péptidos Cíclicos/síntesis química , Profármacos/farmacocinética , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
A series of monocyclic thiazepine inhibitors of interleukin-1beta converting enzyme (ICE) were synthesized in eight steps from commercially available intermediates. In vitro biological evaluation showed the thiazepines to be moderately potent ICE inhibitors, with the most active compound exhibiting an IC50 value of 30 nM in an enzyme inhibition assay. Compounds of this class possessed good selectivity against the related enzymes caspase-3 and caspase-8.
Asunto(s)
Inhibidores de Caspasas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Tiazepinas/síntesis química , Tiazepinas/farmacología , Caspasa 1/metabolismo , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Tiazepinas/químicaRESUMEN
This communication details the synthesis, biological activity, and proposed binding mode of a novel class of tri-cyclic derivatives of 1,2-dihydro-pyrimido[4,5-c]pyridazines 1 and 2. The most potent analogs disclosed showed low nanomolar activity for the inhibition of Lck kinase.
Asunto(s)
Industria Farmacéutica/métodos , Inhibidores Enzimáticos/farmacología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Piridazinas/química , Pirimidinas/química , Ribonucleósidos/química , Diseño de Fármacos , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Linfocitos/metabolismo , Modelos Químicos , Modelos Moleculares , Piridazinas/farmacología , Pirimidinas/farmacología , Relación Estructura-ActividadRESUMEN
A series of C-2, C-8, and N-9 trisubstituted purine based inhibitors of TNF-alpha production are described. The most potent analogs showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell based assay. The SAR of the series was optimized with the aid of X-ray co-crystal structures of these inhibitors bound with mutated p38 (mp38).
Asunto(s)
Purinas/química , Factor de Necrosis Tumoral alfa/química , Línea Celular , Química Farmacéutica , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Lipopolisacáridos/química , Modelos Químicos , Modelos Moleculares , Proteínas Quinasas p38 Activadas por Mitógenos/química , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
Novel 1-(2-acylhydrazinocarbonyl)cycloalkyl carboxamides were designed as peptidomimetic inhibitors of interleukin-1beta converting enzyme (ICE). A short synthesis was developed and moderately potent ICE inhibitors were identified (IC(50) values <100 nM). Most of the synthesized examples were selective for ICE versus the related cysteine proteases caspase-3 and caspase-8, although several dual-acting inhibitors of ICE and caspase-8 were identified. Several of the more potent ICE inhibitors were also shown to inhibit IL-1beta production in a whole cell assay (IC(50) < 500 nM).
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Aminoimidazol Carboxamida/síntesis química , Inhibidores de Caspasas , Hidrazinas/síntesis química , Hidrazinas/farmacología , Aminoimidazol Carboxamida/análogos & derivados , Caspasa 8 , Química Farmacéutica/métodos , Cisteína Endopeptidasas/metabolismo , Industria Farmacéutica/métodos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Modelos QuímicosRESUMEN
A new class of lymphocyte specific tyrosine kinase (lck) inhibitors based on an N-4,6-pyrimidine-N-alkyl-N'-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar inhibition of lck kinase activity as well as IL-2 synthesis from Jurkat cells. One of these analogs, 7i, was shown to be orally efficacious by in vivo testing in a rat adjuvant-induced arthritis study.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Compuestos de Fenilurea/síntesis química , Pirimidinas/química , Administración Oral , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Interleucina-2/biosíntesis , Células Jurkat , Estructura Molecular , Compuestos de Fenilurea/farmacología , RatasRESUMEN
A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on a N-2,4-pyrimidine-N-phenyl-N'-alkyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-alpha production. Two analogs were tested in an in vivo rat iodoacetate model of osteoarthritis and shown to be orally efficacious. X-ray co-crystallization studies with mutated p38alpha showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Osteoartritis/tratamiento farmacológico , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adenosina Trifosfato/química , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/clasificación , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/inducido químicamente , Sitios de Unión , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Enlace de Hidrógeno , Yodoacetatos , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Modelos Moleculares , Estructura Molecular , Osteoartritis/inducido químicamente , Compuestos de Fenilurea/clasificación , Pirimidinas/clasificación , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on an N-2,4-pyrimidine-N-phenyl-N'-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-alpha production. X-ray co-crystallization studies with mutated p38alpha showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction.
Asunto(s)
Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adenosina Trifosfato/química , Sitios de Unión , Cristalografía por Rayos X , Enlace de Hidrógeno , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Modelos Moleculares , Estructura Molecular , Compuestos de Fenilurea/clasificación , Pirimidinas/clasificación , Estereoisomerismo , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Two novel 8,6-fused bicyclic peptidomimetic ring systems were synthesized utilizing olefin metathesis as the key reaction for the formation of the eight-membered ring. Both peptidomimetic scaffolds were further elaborated into potent ICE inhibitors, with numerous compounds exhibiting caspase-1 IC(50)s less than 10nM.
Asunto(s)
Biomimética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Inhibidores de Caspasas , Inhibidores Enzimáticos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Inhibidores Enzimáticos/síntesis química , Humanos , Indicadores y Reactivos , Modelos Moleculares , Conformación MolecularRESUMEN
A novel diazocan containing dipeptide mimetic was synthesized via reductive N-N bond cleavage of a pyrazolidino-pyrazolidine using Raney-Ni and evaluated as an ICE inhibitor. This versatile 8-membered ring containing scaffold possesses an N-5 ring nitrogen that was used to explore structure-activity relationships in a cell-based assay measuring inhibition of interleukin-1beta.
Asunto(s)
Dipéptidos/síntesis química , Interleucina-1/antagonistas & inhibidores , Péptidos Cíclicos/síntesis química , Inhibidores de Caspasas , Dipéptidos/química , Dipéptidos/farmacología , Evaluación Preclínica de Medicamentos , Concentración 50 Inhibidora , Interleucina-1/biosíntesis , Conformación Molecular , Imitación Molecular , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Pirazoles/química , Relación Estructura-ActividadRESUMEN
4-Aryl-5-pyrimidyl based cytokine synthesis inhibitors that contain a novel monocyclic, pyrazolone heterocyclic core are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production. One of the compounds (6e) was found to be efficacious in the rat iodoacetate (RIA) in vivo model of osteoarthritis. The X-ray crystal structure of a pyrazolone inhibitor cocrystallized with mutated p38 (mp38) is presented.
Asunto(s)
Citocinas/antagonistas & inhibidores , Citocinas/biosíntesis , Pirazolonas/síntesis química , Pirazolonas/farmacología , Animales , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Cinética , Lipopolisacáridos/farmacología , Modelos Moleculares , Conformación Molecular , Osteoartritis/prevención & control , Pirazolonas/química , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesis , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
4-Aryl-3-pyridyl and 4-aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel isoxazolone five-membered heterocyclic core are described. Many showed sub-micromolar activity against lipopolysaccharide-induced TNF-alpha production.