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1.
Bioorg Med Chem Lett ; 25(17): 3644-9, 2015 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-26189078

RESUMEN

The discovery and optimization of a series of small molecule EZH2 inhibitors is described. Starting from dimethylpyridone HTS hit (2), a series of indole-based EZH2 inhibitors were identified. Biochemical potency and microsomal stability were optimized during these studies and afforded compound 22. This compound demonstrates nanomolar levels of biochemical potency (IC50=0.002 µM), cellular potency (EC50=0.080 µM), and afforded tumor regression when dosed (200 mpk SC BID) in an EZH2 dependent tumor xenograft model.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Indoles/química , Complejo Represivo Polycomb 2/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Línea Celular Tumoral , Técnicas de Química Sintética , Diseño de Fármacos , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Estabilidad de Medicamentos , Proteína Potenciadora del Homólogo Zeste 2 , Células HeLa/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Terapia Molecular Dirigida/métodos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
2.
BMC Infect Dis ; 13: 250, 2013 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-23721325

RESUMEN

BACKGROUND: Disease progression in the absence of therapy varies significantly in HIV-1 infected individuals. Both viral and host cellular molecules are implicated; however, the exact role of these factors and/or the mechanism involved remains elusive. To understand how microRNAs (miRNAs), which are regulators of transcription and translation, influence host cellular gene expression (mRNA) during HIV-1 infection, we performed a comparative miRNA and mRNA microarray analysis using PBMCs obtained from infected individuals with distinct viral load and CD4 counts. METHODS: RNA isolated from PBMCs obtained from HIV-1 seronegative and HIV-1 positive individuals with distinct viral load and CD4 counts were assessed for miRNA and mRNA profile. Selected miRNA and mRNA transcripts were validated using in vivo and in vitro infection model. RESULTS: Our results indicate that HIV-1 positive individuals with high viral load (HVL) showed a dysregulation of 191 miRNAs and 309 mRNA transcripts compared to the uninfected age and sex matched controls. The miRNAs miR-19b, 146a, 615-3p, 382, 34a, 144 and 155, that are known to target innate and inflammatory factors, were significantly upregulated in PBMCs with high viral load, as were the inflammatory molecules CXCL5, CCL2, IL6 and IL8, whereas defensin, CD4, ALDH1, and Neurogranin (NRGN) were significantly downregulated. Using the transcriptome profile and predicted target genes, we constructed the regulatory networks of miRNA-mRNA pairs that were differentially expressed between control, LVL and HVL subjects. The regulatory network revealed an inverse correlation of several miRNA-mRNA pair expression patterns, suggesting HIV-1 mediated transcriptional regulation is in part likely through miRNA regulation. CONCLUSIONS: Results from our studies indicate that gene expression is significantly altered in PBMCs in response to virus replication. It is interesting to note that the infected individuals with low or undetectable viral load exhibit a gene expression profile very similar to control or uninfected subjects. Importantly, we identified several new mRNA targets (Defensin, Neurogranin, AIF) as well as the miRNAs that could be involved in regulating their expression through the miRNA-mRNA interaction.


Asunto(s)
Recuento de Linfocito CD4 , Infecciones por VIH/genética , VIH-1/aislamiento & purificación , MicroARNs/análisis , ARN Mensajero/análisis , Adulto , Anciano , Análisis por Conglomerados , Citocinas/análisis , Citocinas/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Infecciones por VIH/inmunología , Infecciones por VIH/metabolismo , Interacciones Huésped-Patógeno , Humanos , Leucocitos Mononucleares/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Reproducibilidad de los Resultados , Estadísticas no Paramétricas , Transcriptoma , Carga Viral
3.
Eukaryot Cell ; 10(8): 1100-9, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21666072

RESUMEN

A screening procedure was used to identify cell fusion (hyphal anastomosis) mutants in the Neurospora crassa single gene deletion library. Mutants with alterations in 24 cell fusion genes required for cell fusion between conidial anastomosis tubes (CATs) were identified and characterized. The cell fusion genes identified included 14 genes that are likely to function in signal transduction pathways needed for cell fusion to occur (mik-1, mek-1, mak-1, nrc-1, mek-2, mak-2, rac-1, pp2A, so/ham-1, ham-2, ham-3, ham-5, ham-9, and mob3). The screening experiments also identified four transcription factors that are required for cell fusion (adv-1, ada-3, rco-1, and snf5). Three genes encoding proteins likely to be involved in the process of vesicular trafficking were also identified as needed for cell fusion during the screening (amph-1, ham-10, pkr1). Three of the genes identified by the screening procedure, ham-6, ham-7, and ham-8, encode proteins that might function in mediating the plasma membrane fusion event. Three of the putative signal transduction proteins, three of the transcription factors, the three putative vesicular trafficking proteins, and the three proteins that might function in mediating cell fusion had not been identified previously as required for cell fusion.


Asunto(s)
Fusión Celular , Hifa/citología , Neurospora crassa/citología , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Técnicas de Inactivación de Genes , Estudios de Asociación Genética , Hifa/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Neurospora crassa/genética , Fenotipo , Esporas Fúngicas/citología , Esporas Fúngicas/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Vesículas Transportadoras/genética , Vesículas Transportadoras/metabolismo
4.
ACS Med Chem Lett ; 11(6): 1213-1220, 2020 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-32551003

RESUMEN

Leveraging the catalytic machinery of LSD1 (KDM1A), a series of covalent styrenylcyclopropane LSD1 inhibitors were identified. These inhibitors represent a new class of mechanism-based inhibitors that target and covalently label the FAD cofactor of LSD1. The series was rapidly progressed to potent biochemical and cellular LSD1 inhibitors with good physical properties. This effort resulted in the identification of 34, a highly potent (<4 nM biochemical, 2 nM cell, and 1 nM GI50), and selective LSD1 inhibitor. In-depth kinetic profiling of 34 confirmed its covalent mechanism of action, validated the styrenylcyclopropane as an FAD-directed warhead, and demonstrated that the potency of this inhibitor is driven by improved non-covalent binding (K I). 34 demonstrated robust cell-killing activity in a panel of AML cell lines and robust antitumor activity in a Kasumi-1 xenograft model of AML when dosed orally at 1.5 mg/kg once daily.

5.
J Med Chem ; 59(21): 9928-9941, 2016 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-27739677

RESUMEN

Polycomb repressive complex 2 (PRC2) has been shown to play a major role in transcriptional silencing in part by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function correlates with certain malignancies and poor prognosis. EZH2 is the catalytic engine of the PRC2 complex and thus represents a key candidate oncology target for pharmacological intervention. Here we report the optimization of our indole-based EZH2 inhibitor series that led to the identification of CPI-1205, a highly potent (biochemical IC50 = 0.002 µM, cellular EC50 = 0.032 µM) and selective inhibitor of EZH2. This compound demonstrates robust antitumor effects in a Karpas-422 xenograft model when dosed at 160 mg/kg BID and is currently in Phase I clinical trials. Additionally, we disclose the co-crystal structure of our inhibitor series bound to the human PRC2 complex.


Asunto(s)
Antineoplásicos/farmacología , Ensayos Clínicos Fase I como Asunto , Inhibidores Enzimáticos/farmacología , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , Indoles/farmacología , Linfoma de Células B/tratamiento farmacológico , Piperidinas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Indoles/síntesis química , Indoles/química , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Piperidinas/síntesis química , Piperidinas/química , Ratas , Relación Estructura-Actividad
6.
Chem Biol ; 21(11): 1463-75, 2014 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-25457180

RESUMEN

The histone lysine methyltransferase (MT) Enhancer of Zeste Homolog 2 (EZH2) is considered an oncogenic driver in a subset of germinal center B-cell-like diffuse large B cell lymphoma (GCB-DLBCL) and follicular lymphoma due to the presence of recurrent, monoallelic mutations in the EZH2 catalytic domain. These genomic data suggest that targeting the EZH2 MT activity is a valid therapeutic strategy for the treatment of lymphoma patients with EZH2 mutations. Here we report the identification of highly potent and selective EZH2 small molecule inhibitors, their validation by a cellular thermal shift assay, application across a large cell panel representing various non-Hodgkin's lymphoma (NHL) subtypes, and their efficacy in EZH2mutant-containing GCB-DLBCL xenograft models. Surprisingly, our EZH2 inhibitors selectively affect the turnover of trimethylated, but not monomethylated histone H3 lysine 27 at pharmacologically relevant doses. Importantly, we find that these inhibitors are broadly efficacious also in NHL models with wild-type EZH2.


Asunto(s)
Apoptosis/efectos de los fármacos , Inhibidores Enzimáticos/toxicidad , Histonas/metabolismo , Complejo Represivo Polycomb 2/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/toxicidad , Secuencia de Aminoácidos , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Histonas/química , Humanos , Cinética , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Linfoma no Hodgkin/metabolismo , Linfoma no Hodgkin/patología , Metilación , Ratones , Ratones Desnudos , Mutación , Péptidos/análisis , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Trasplante Heterólogo
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