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1.
J Med Case Rep ; 13(1): 227, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31345262

RESUMO

BACKGROUND: Syphilis is a sexually transmitted bacterial infection of the spirochete, Treponema pallidum. While primary syphilis often involves genitalia, oral manifestations are observed in a subset of patients. These lesions are often associated with submandibular and cervical lymphadenopathy. This is a case report of a primary syphilitic lesion located on the hard palate of the oral cavity, with only a very few cases described previously. CASE PRESENTATION: We describe a rare case of syphilis in a 59-year-old African American man presenting with subjective fevers, chills, marked submental lymphadenopathy, a diffuse skin rash, and an ulcer of the hard palate. CONCLUSIONS: This case report demonstrates the importance of maintaining a high index of suspicion for syphilitic infection when a patient presents with nonspecific symptoms, a diffuse rash, and an oral lesion.


Assuntos
Úlceras Orais/etiologia , Sífilis/complicações , Idoso , Progressão da Doença , Exantema/etiologia , Humanos , Masculino , Palato Duro , Sífilis/diagnóstico , Sífilis/fisiopatologia , Treponema pallidum/isolamento & purificação
2.
Proc Natl Acad Sci U S A ; 113(46): 13162-13167, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27799547

RESUMO

Multiple myeloma (MM) has proven clinically susceptible to modulation of pathways of protein homeostasis. Blockade of proteasomal degradation of polyubiquitinated misfolded proteins by the proteasome inhibitor bortezomib (BTZ) achieves responses and prolongs survival in MM, but long-term treatment with BTZ leads to drug-resistant relapse in most patients. In a proof-of-concept study, we previously demonstrated that blocking aggresomal breakdown of polyubiquitinated misfolded proteins with the histone deacetylase 6 (HDAC6) inhibitor tubacin enhances BTZ-induced cytotoxicity in MM cells in vitro. However, these foundational studies were limited by the pharmacologic liabilities of tubacin as a chemical probe with only in vitro utility. Emerging from a focused library synthesis, a potent, selective, and bioavailable HDAC6 inhibitor, WT161, was created to study the mechanism of action of HDAC6 inhibition in MM alone and in combination with BTZ. WT161 in combination with BTZ triggers significant accumulation of polyubiquitinated proteins and cell stress, followed by caspase activation and apoptosis. More importantly, this combination treatment was effective in BTZ-resistant cells and in the presence of bone marrow stromal cells, which have been shown to mediate MM cell drug resistance. The activity of WT161 was confirmed in our human MM cell xenograft mouse model and established the framework for clinical trials of the combination treatment to improve patient outcomes in MM.


Assuntos
Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/uso terapêutico , Compostos de Terfenil/uso terapêutico , Anilidas/farmacologia , Anilidas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Bortezomib/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Masculino , Camundongos , Mieloma Múltiplo/metabolismo , Inibidores de Proteassoma/farmacologia , Compostos de Terfenil/farmacologia , Tubulina (Proteína)/metabolismo , Células Tumorais Cultivadas
3.
ACS Med Chem Lett ; 7(10): 929-932, 2016 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-27774131

RESUMO

A novel, isoform-selective inhibitor of histone deacetylase 8 (HDAC8) has been discovered by the repurposing of a diverse compound collection. Medicinal chemistry optimization led to the identification of a highly potent (0.8 nM) and selective inhibitor of HDAC8.

4.
Mol Cell ; 56(2): 219-231, 2014 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-25263595

RESUMO

Proinflammatory stimuli elicit rapid transcriptional responses via transduced signals to master regulatory transcription factors. To explore the role of chromatin-dependent signal transduction in the atherogenic inflammatory response, we characterized the dynamics, structure, and function of regulatory elements in the activated endothelial cell epigenome. Stimulation with tumor necrosis factor alpha prompted a dramatic and rapid global redistribution of chromatin activators to massive de novo clustered enhancer domains. Inflammatory super enhancers formed by nuclear factor-kappa B accumulate at the expense of immediately decommissioned, basal endothelial super enhancers, despite persistent histone hyperacetylation. Mass action of enhancer factor redistribution causes momentous swings in transcriptional initiation and elongation. A chemical genetic approach reveals a requirement for BET bromodomains in communicating enhancer remodeling to RNA Polymerase II and orchestrating the transition to the inflammatory cell state, demonstrated in activated endothelium and macrophages. BET bromodomain inhibition abrogates super enhancer-mediated inflammatory transcription, atherogenic endothelial responses, and atherosclerosis in vivo.


Assuntos
Aterosclerose/genética , Inflamação/genética , Subunidade p50 de NF-kappa B/imunologia , Proteínas Nucleares/antagonistas & inibidores , Fator de Transcrição RelA/imunologia , Fatores de Transcrição/antagonistas & inibidores , Acetilação , Animais , Aterosclerose/imunologia , Azepinas/farmacologia , Adesão Celular/imunologia , Movimento Celular/genética , Movimento Celular/imunologia , Células Cultivadas , Cromatina/genética , Selectina E/biossíntese , Células Endoteliais , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Elementos Facilitadores Genéticos , Histonas/metabolismo , Humanos , Inflamação/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Subunidade p50 de NF-kappa B/genética , Proteínas Nucleares/imunologia , Ligação Proteica , RNA Polimerase II/genética , Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição SOXF/genética , Transdução de Sinais , Fator de Transcrição RelA/genética , Fatores de Transcrição/imunologia , Iniciação da Transcrição Genética , Transcrição Genética/efeitos dos fármacos , Triazóis/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Molécula 1 de Adesão de Célula Vascular/biossíntese
5.
Chem Biol ; 20(5): 713-25, 2013 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-23706636

RESUMO

While cytotoxic chemotherapy remains the hallmark of cancer treatment, intensive regimens fall short in many malignancies, including high-risk neuroblastoma. One alternative strategy is to therapeutically promote tumor differentiation. We created a gene expression signature to measure neuroblast maturation, adapted it to a high-throughput platform, and screened a diversity oriented synthesis-generated small-molecule library for differentiation inducers. We identified BRD8430, containing a nine-membered lactam, an ortho-amino anilide functionality, and three chiral centers, as a selective class I histone deacetylase (HDAC) inhibitor (HDAC1 > 2 > 3). Further investigation demonstrated that selective HDAC1/HDAC2 inhibition using compounds or RNA interference induced differentiation and decreased viability in neuroblastoma cell lines. Combined treatment with 13-cis retinoic acid augmented these effects and enhanced activation of retinoic acid signaling. Therefore, by applying a chemical genomic screening approach, we identified selective HDAC1/HDAC2 inhibition as a strategy to induce neuroblastoma differentiation.


Assuntos
Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 2/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Lactamas/farmacologia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/enzimologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/química , Humanos , Lactamas/química , Neuroblastoma/genética , Neuroblastoma/patologia , Tretinoína/metabolismo
6.
Bioorg Med Chem Lett ; 23(11): 3346-8, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23591111

RESUMO

We have synthesized a ß-cyclodextrin (ßCD)-capped histone deacetylase (HDAC) inhibitor 3 containing an alkyl linker and a zinc-binding hydroxamic acid motif. Biological evaluation (HDAC inhibition studies) of 3 enabled us to establish the effect of replacing an aryl cap (in SAHA (vorinostat,)) 1 by a large saccharidic scaffold "cap". HDAC inhibition was observed for 3, to a lesser extent than SAHA, and rationalized by molecular docking into the active site of HDAC8. However, compound 3 displayed no cellular activity.


Assuntos
Inibidores de Histona Desacetilases/química , Histona Desacetilases/química , Proteínas Repressoras/química , beta-Ciclodextrinas/química , Sítios de Ligação , Linhagem Celular Tumoral , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/química , Simulação de Acoplamento Molecular , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Proteínas Repressoras/metabolismo , Vorinostat , Zinco/química , beta-Ciclodextrinas/metabolismo
7.
Cell ; 151(1): 56-67, 2012 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-23021215

RESUMO

Elevated expression of the c-Myc transcription factor occurs frequently in human cancers and is associated with tumor aggression and poor clinical outcome. The effect of high levels of c-Myc on global gene regulation is poorly understood but is widely thought to involve newly activated or repressed "Myc target genes." We report here that in tumor cells expressing high levels of c-Myc the transcription factor accumulates in the promoter regions of active genes and causes transcriptional amplification, producing increased levels of transcripts within the cell's gene expression program. Thus, rather than binding and regulating a new set of genes, c-Myc amplifies the output of the existing gene expression program. These results provide an explanation for the diverse effects of oncogenic c-Myc on gene expression in different tumor cells and suggest that transcriptional amplification reduces rate-limiting constraints for tumor cell growth and proliferation.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Elementos Facilitadores Genéticos , Humanos , Neoplasias/patologia , Regiões Promotoras Genéticas , Transcrição Genética
8.
Blood ; 120(14): 2843-52, 2012 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-22904298

RESUMO

We investigated the therapeutic potential of JQ1, an inhibitor of the BET class of human bromodomain proteins, in B-cell acute lymphoblastic leukemia (B-ALL). We show that JQ1 potently reduces the viability of B-ALL cell lines with high-risk cytogenetics. Among the most sensitive were lines with rearrangements of CRLF2, which is overexpressed in ~ 10% of B-ALL. CRLF2 heterodimerizes with the IL7 receptor (IL7R) and signals through JAK2, JAK1, and STAT5 to drive proliferation and suppress apoptosis. As previously observed, JQ1 induced the down-regulation of MYC transcription, the loss of BRD4 at the MYC promoter, and the reduced expression of c-Myc target genes. Strikingly, JQ1 also down-regulated IL7R transcription, depleted BRD4 from the IL7R promoter, and reduced JAK2 and STAT5 phosphorylation. Genome-wide expression profiling demonstrated a restricted effect of JQ1 on transcription, with MYC and IL7R being among the most down-regulated genes. Indeed, IL7R was the only cytokine receptor in CRLF2-rearranged B-ALL cells significantly down-regulated by JQ1 treatment. In mice xenografted with primary human CRLF2-rearranged B-ALL, JQ1 suppressed c-Myc expression and STAT5 phosphorylation and significantly prolonged survival. Thus, bromodomain inhibition is a promising therapeutic strategy for B-ALL as well as other conditions dependent on IL7R signaling.


Assuntos
Azepinas/uso terapêutico , Proteínas Nucleares/antagonistas & inibidores , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores de Citocinas/genética , Receptores de Interleucina-7/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Triazóis/uso terapêutico , Animais , Apoptose , Linfócitos B/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Imunoprecipitação da Cromatina , Citometria de Fluxo , Perfilação da Expressão Gênica , Rearranjo Gênico , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Análise de Sequência com Séries de Oligonucleotídeos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogênicas c-myc/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Interleucina-7/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Exp Med ; 209(2): 259-73, 2012 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-22271575

RESUMO

Enzymatic inhibitors of Janus kinase 2 (JAK2) are in clinical development for the treatment of myeloproliferative neoplasms (MPNs), B cell acute lymphoblastic leukemia (B-ALL) with rearrangements of the cytokine receptor subunit cytokine receptor-like factor 2 (CRLF2), and other tumors with constitutive JAK2 signaling. In this study, we identify G935R, Y931C, and E864K mutations within the JAK2 kinase domain that confer resistance across a panel of JAK inhibitors, whether present in cis with JAK2 V617F (observed in MPNs) or JAK2 R683G (observed in B-ALL). G935R, Y931C, and E864K do not reduce the sensitivity of JAK2-dependent cells to inhibitors of heat shock protein 90 (HSP90), which promote the degradation of both wild-type and mutant JAK2. HSP90 inhibitors were 100-1,000-fold more potent against CRLF2-rearranged B-ALL cells, which correlated with JAK2 degradation and more extensive blockade of JAK2/STAT5, MAP kinase, and AKT signaling. In addition, the HSP90 inhibitor AUY922 prolonged survival of mice xenografted with primary human CRLF2-rearranged B-ALL further than an enzymatic JAK2 inhibitor. Thus, HSP90 is a promising therapeutic target in JAK2-driven cancers, including those with genetic resistance to JAK enzymatic inhibitors.


Assuntos
Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Isoxazóis/farmacologia , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Leucemia de Células B/enzimologia , Transtornos Mieloproliferativos/enzimologia , Resorcinóis/farmacologia , Transdução de Sinais/fisiologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Primers do DNA/genética , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Immunoblotting , Imuno-Histoquímica , Isoxazóis/uso terapêutico , Janus Quinase 2/metabolismo , Leucemia de Células B/tratamento farmacológico , Leucemia de Células B/genética , Luciferases , Camundongos , Camundongos Endogâmicos BALB C , Mutagênese , Mutação de Sentido Incorreto/genética , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Fosforilação , RNA Interferente Pequeno/genética , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Resorcinóis/uso terapêutico , Microtomografia por Raio-X
10.
Cell ; 146(6): 904-17, 2011 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-21889194

RESUMO

MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative coactivator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Mieloma Múltiplo/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Animais , Antineoplásicos/química , Azepinas/química , Azepinas/farmacologia , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Camundongos , Proteínas Nucleares/química , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-myc/genética , Ativação Transcricional/efeitos dos fármacos , Triazóis/química , Triazóis/farmacologia
11.
ACS Med Chem Lett ; 2(5): 358-362, 2011 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-21572592

RESUMO

N(1)-Hydroxy-N(8)-ferrocenyloctanediamide, JAHA (7), an organometallic analogue of SAHA containing a ferrocenyl group as a phenyl bioisostere, displays nanomolar inhibition of class I HDACs, excellent selectivity over class IIa HDACs, and anticancer action in intact cells (IC(50) = 2.4 µM, MCF7 cell line). Molecular docking studies of 7 in HDAC8 (a,b) suggested that the ferrocenyl moiety in 7 can overlap with the aryl cap of SAHA and should display similar HDAC inhibition, which was borne out in an in vitro assay (IC(50) values against HDAC8 (µM, SD in parentheses): SAHA, 1.41 (0.15); 7, 1.36 (0.16). Thereafter, a small library of related JAHA analogues has been synthesized, and preliminary SAR studies are presented. IC(50) values as low as 90 pM toward HDAC6 (class IIb) have been determined, highlighting the excellent potential of JAHAs as bioinorganic probes.

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