RESUMO
[This corrects the article DOI: 10.18632/oncotarget.27589.].
RESUMO
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.
RESUMO
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.
Assuntos
Alcaloides/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Quadruplex G/efeitos dos fármacos , Indóis/química , Indóis/farmacologia , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Quinolinas/química , Quinolinas/farmacologia , Antineoplásicos/síntese química , Regulação da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Indóis/síntese química , Concentração Inibidora 50 , Neoplasias/metabolismo , Regiões Promotoras Genéticas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/genética , Quinolinas/síntese química , Elementos Silenciadores TranscricionaisRESUMO
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.
RESUMO
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.
Assuntos
Janus Quinase 3/antagonistas & inibidores , Pirimidinas/síntese química , Pirróis/síntese química , Doenças Autoimunes/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Imunidade/efeitos dos fármacos , Janus Quinase 2/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Caprolactama/síntese química , Inibidores de Caspase , Inibidores Enzimáticos/farmacologia , Serpinas/síntese química , Proteínas Virais/síntese química , Animais , Disponibilidade Biológica , Caprolactama/química , Caprolactama/farmacologia , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ligação de Hidrogênio , Interleucina-1beta/metabolismo , Masculino , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Serpinas/farmacologia , Relação Estrutura-Atividade , Proteínas Virais/farmacologiaRESUMO
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).
Assuntos
Benzimidazóis/química , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Ligação de Hidrogênio , Concentração Inibidora 50 , Interleucina-2/metabolismo , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/síntese química , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-hck/química , Proteínas Proto-Oncogênicas c-hck/metabolismo , Relação Estrutura-AtividadeRESUMO
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%).
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Inibidores de Caspase , Peptídeos Cíclicos/farmacologia , Animais , Disponibilidade Biológica , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Meia-Vida , Concentração Inibidora 50 , Mimetismo Molecular , Peptídeos Cíclicos/síntese química , Pró-Fármacos/farmacocinética , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
A new class of pyrimidine-based Janus tyrosine kinase 3 (JAK3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK3.
Assuntos
Janus Quinase 3/antagonistas & inibidores , Pirimidinas/química , Pirimidinas/farmacologiaRESUMO
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.
Assuntos
Inibidores de Caspase , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Tiazepinas/síntese química , Tiazepinas/farmacologia , Caspase 1/metabolismo , Cristalografia por Raios X , Inibidores Enzimáticos/química , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Tiazepinas/químicaRESUMO
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).
Assuntos
Purinas/química , Fator de Necrose Tumoral alfa/química , Linhagem Celular , Química Farmacêutica , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Lipopolissacarídeos/química , Modelos Químicos , Modelos Moleculares , Proteínas Quinases p38 Ativadas por Mitógeno/química , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
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).
Assuntos
Amidas/síntese química , Amidas/farmacologia , Aminoimidazol Carboxamida/síntese química , Inibidores de Caspase , Hidrazinas/síntese química , Hidrazinas/farmacologia , Aminoimidazol Carboxamida/análogos & derivados , Caspase 8 , Química Farmacêutica/métodos , Cisteína Endopeptidases/metabolismo , Indústria Farmacêutica/métodos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Modelos QuímicosRESUMO
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.
Assuntos
Indústria Farmacêutica/métodos , Inibidores Enzimáticos/farmacologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Piridazinas/química , Pirimidinas/química , Ribonucleosídeos/química , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Linfócitos/metabolismo , Modelos Químicos , Modelos Moleculares , Piridazinas/farmacologia , Pirimidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores Enzimáticos/síntese química , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Compostos de Fenilureia/síntese química , Pirimidinas/química , Administração Oral , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Interleucina-2/biossíntese , Células Jurkat , Estrutura Molecular , Compostos de Fenilureia/farmacologia , RatosRESUMO
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.
Assuntos
Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Trifosfato de Adenosina/química , Sítios de Ligação , Cristalografia por Raios X , Ligação de Hidrogênio , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Modelos Moleculares , Estrutura Molecular , Compostos de Fenilureia/classificação , Pirimidinas/classificação , Estereoisomerismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossínteseRESUMO
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.
Assuntos
Artrite Experimental/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Trifosfato de Adenosina/química , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/classificação , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/induzido quimicamente , Sítios de Ligação , Cristalografia por Raios X , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Ligação de Hidrogênio , Iodoacetatos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Modelos Moleculares , Estrutura Molecular , Osteoartrite/induzido quimicamente , Compostos de Fenilureia/classificação , Pirimidinas/classificação , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossínteseRESUMO
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.
Assuntos
Biomimética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Inibidores de Caspase , Inibidores Enzimáticos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Inibidores Enzimáticos/síntese química , Humanos , Indicadores e Reagentes , Modelos Moleculares , Conformação MolecularRESUMO
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.
Assuntos
Dipeptídeos/síntese química , Interleucina-1/antagonistas & inibidores , Peptídeos Cíclicos/síntese química , Inibidores de Caspase , Dipeptídeos/química , Dipeptídeos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Concentração Inibidora 50 , Interleucina-1/biossíntese , Conformação Molecular , Mimetismo Molecular , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Pirazolonas/síntese química , Pirazolonas/farmacologia , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Cinética , Lipopolissacarídeos/farmacologia , Modelos Moleculares , Conformação Molecular , Osteoartrite/prevenção & controle , Pirazolonas/química , Ratos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
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.