RESUMEN
A new compound, a derivative of 3,4,5-trimethoxy-N-phenyl benzamide bearing an 8''-methylimidazopyridine moiety, is found to demonstrate neuroprotective effects by preventing cell death caused by oxidative stress. The compound possesses high solubility and metabolic stability, and inhibits MPTP-induced effects in vivo, indicating high potential as a therapeutic drug for Parkinson's disease.
RESUMEN
Ebolaviruses and marburgviruses, members of the family Filoviridae, are known to cause fatal diseases often associated with hemorrhagic fever. Recent outbreaks of Ebola virus disease in West African countries and the Democratic Republic of the Congo have made clear the urgent need for the development of therapeutics and vaccines against filoviruses. Using replication-incompetent vesicular stomatitis virus (VSV) pseudotyped with the Ebola virus (EBOV) envelope glycoprotein (GP), we screened a chemical compound library to obtain new drug candidates that inhibit filoviral entry into target cells. We discovered a biaryl sulfonamide derivative that suppressed in vitro infection mediated by GPs derived from all known human-pathogenic filoviruses. To determine the inhibitory mechanism of the compound, we monitored each entry step (attachment, internalization, and membrane fusion) using lipophilic tracer-labeled ebolavirus-like particles and found that the compound efficiently blocked fusion between the viral envelope and the endosomal membrane during cellular entry. However, the compound did not block the interaction of GP with the Niemann-Pick C1 protein, which is believed to be the receptor of filoviruses. Using replication-competent VSVs pseudotyped with EBOV GP, we selected escape mutants and identified two EBOV GP amino acid residues (positions 47 and 66) important for the interaction with this compound. Interestingly, these amino acid residues were located at the base region of the GP trimer, suggesting that the compound might interfere with the GP conformational change required for membrane fusion. These results suggest that this biaryl sulfonamide derivative is a novel fusion inhibitor and a possible drug candidate for the development of a pan-filovirus therapeutic.
Asunto(s)
Filoviridae/efectos de los fármacos , Sulfonamidas/química , Sulfonamidas/farmacología , Internalización del Virus/efectos de los fármacos , Animales , Chlorocebus aethiops , Descubrimiento de Drogas , Ebolavirus/efectos de los fármacos , Filoviridae/clasificación , Infecciones por Filoviridae/tratamiento farmacológico , Infecciones por Filoviridae/virología , Células HEK293 , Fiebre Hemorrágica Ebola/tratamiento farmacológico , Humanos , Enfermedad del Virus de Marburg/tratamiento farmacológico , Marburgvirus/efectos de los fármacos , Receptores Virales/metabolismo , Células VeroRESUMEN
The Notch receptor serves a fundamental role in the regulation of cell fate determination through intracellular signal transmission. Mutation of the Notch receptor results in abnormal active signaling, leading to the development of diseases involving abnormal cell growth, including malignant tumors. Therefore, the Notch signaling pathway is a useful pharmacological target for the treatment of cancer. In the present study, a compound screening system was designed to identify inhibitors of the Notch signaling targeting Notch intracellular domain (NICD). A total of 9,600 compounds were analyzed using the Michigan Cancer Foundation7 (MCF7) human breast adenocarcinoma cell line and the SHSY5Y human neuroblastoma cell line with the reporter assay system using an artificial protein encoding a partial Notch carboxylterminal fragment fused to the Gal4 DNAbinding domain. The molecular mechanism underlying the inhibition of Notch signaling by a hit compound was further validated using biochemical and cell biological approaches. Using the screening system, a potential candidate, Notch signaling inhibitor1 (NSI1), was isolated which showed 50% inhibition at 6.1 µM in an exogenous Notch signaling system. In addition, NSI1 suppressed the nuclear translocation of NICD and endogenous gene expression of hairy and enhancer of split1, indicating that NSI1 specifically targets Notch. Notably, NSI1 suppressed the cell viability of MCF7 cells and another human breast adenocarcinoma cell line, MDAMB231 exhibiting constitutive and high Notch signaling activity, whereas no significant effect was observed in the SHSY5Y cells bearing a lower Notch signaling activity. NSI1 significantly suppressed the viability of SHSY5Y cells expressing exogenous human Notch1. These results indicate that NSI1 is a novel Notch signaling inhibitor and suggest its potential as a useful drug for the treatment of diseases induced by constitutively active Notch signaling.
Asunto(s)
Dominios y Motivos de Interacción de Proteínas , Receptores Notch/metabolismo , Transducción de Señal/efectos de los fármacos , Línea Celular Tumoral , Núcleo Celular , Supervivencia Celular/efectos de los fármacos , Descubrimiento de Drogas/métodos , Humanos , Unión Proteica , Transporte de Proteínas , Receptores Notch/química , Receptores Notch/genéticaRESUMEN
AU-rich elements (ARE) exist in the 3'-untranslated regions of the mRNA transcribed from cell growth-related genes such as proto-oncogenes, cyclin-related genes, and growth factors. HuR binds and stabilizes ARE-mRNA. HuR is expressed abundantly in cancer cells and related malignant phenotypes. HuR knockdown attenuates the malignant phenotype of oral cancer cells. In this study, we screened 1570 compounds in the approved drug library by differential scanning fluorimetry (DSF) to discover a HuR-targeted compound. Firstly, 55 compounds were selected by DSF. Then, 8 compounds that showed a shift in the melting temperature value in a concentration-dependent manner were selected by DSF. Of them, suramin, an anti-trypanosomal drug, binds to HuR, exhibiting fast-on and fast-off kinetic behavior on surface plasmon resonance (SPR). We confirmed that suramin significantly decreased mRNA and protein expression of cyclin A2 and cyclin B1. The cyclin A2 and cyclin B1 mRNAs were destabilized by suramin. Furthermore, the motile and invasive activities of a tongue carcinoma cell line treated with suramin were markedly lower than those of control cells. The above findings suggest that suramin binds to HuR and inhibits its function. We also showed that the anticancer effects of suramin were caused by the inhibition of HuR function, indicating its potential as a novel therapeutic agent in the treatment of oral cancer. Our results suggest that suramin, via its different mechanism, may effectively suppress progressive oral cancer that cannot be controlled using other anticancer agents.
Asunto(s)
Antineoplásicos/farmacología , Proteína 1 Similar a ELAV/metabolismo , Suramina/farmacología , Neoplasias de la Lengua/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Proteína 1 Similar a ELAV/genética , Humanos , Bibliotecas de Moléculas Pequeñas , Neoplasias de la Lengua/tratamiento farmacológico , Cicatrización de Heridas/efectos de los fármacosRESUMEN
We accomplished divergent synthesis of potent kinase inhibitor BAY 61-3606 (1) and 27 derivatives via conjugation of imidazo[1,2-c]pyrimidine and indole ring compounds with aromatic (including pyridine) derivatives by means of palladium-catalyzed cross-coupling reaction. Spleen tyrosine kinase (Syk) and germinal center kinase (Gck, MAP4K2) inhibition assays showed that some of the synthesized compounds were selective Gck inhibitors.
Asunto(s)
Imidazoles/química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinas/química , Catálisis , Evaluación Preclínica de Medicamentos , Quinasas del Centro Germinal , Humanos , Imidazoles/síntesis química , Imidazoles/metabolismo , Indoles/química , Concentración 50 Inhibidora , Niacinamida/análogos & derivados , Niacinamida/química , Niacinamida/metabolismo , Paladio/química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Pirimidinas/síntesis química , Pirimidinas/metabolismo , Relación Estructura-Actividad , Quinasa Syk/antagonistas & inhibidores , Quinasa Syk/metabolismoRESUMEN
Glioblastoma (GBM), one of the most malignant human cancers, frequently recurs despite multimodal treatment with surgery and chemo/radiotherapies. GBM-initiating cells (GICs) are the likely cell-of-origin in recurrences, as they proliferate indefinitely, form tumors in vivo, and are resistant to chemo/radiotherapies. It is therefore crucial to find chemicals that specifically kill GICs. We established temozolomide (the standard medicine for GBM)-resistant GICs (GICRs) and used the cells for chemical screening. Here, we identified 1-(3-C-ethynyl-ß-d-ribopentofuranosyl) uracil (EUrd) as a selective drug for targeting GICRs. EUrd induced the death in GICRs more effectively than their parental GICs, while it was less toxic to normal neural stem cells. We demonstrate that the cytotoxic effect of EUrd on GICRs partly depended on the increased expression of uridine-cytidine kinase-like 1 (UCKL1) and the decreased one of 5'-nucleotidase cytosolic III (NT5C3), which regulate uridine-monophosphate synthesis positively and negatively respectively. Together, these findings suggest that EUrd can be used as a new therapeutic drug for GBM with the expression of surrogate markers UCKL1 and NT5C3. Stem Cells 2016;34:2016-2025.
Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Dacarbazina/análogos & derivados , Evaluación Preclínica de Medicamentos , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Uracilo/uso terapéutico , Uridina/análogos & derivados , 5'-Nucleotidasa/metabolismo , Animales , Carcinogénesis/metabolismo , Carcinogénesis/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Glicoproteínas/metabolismo , Humanos , Ratones SCID , Temozolomida , Uracilo/farmacología , Uridina/farmacología , Uridina/uso terapéuticoRESUMEN
Substituting a carbon atom with a nitrogen atom (nitrogen substitution) on an aromatic ring in our leads 11a and 13g by applying nitrogen scanning afforded a set of compounds that improved not only the solubility but also the metabolic stability. The impact after nitrogen substitution on interactions between a derivative and its on- and off-target proteins (Raf/MEK, CYPs, and hERG channel) was also detected, most of them contributing to weaker interactions. After identifying the positions that kept inhibitory activity on HCT116 cell growth and Raf/MEK, compound 1 (CH5126766/RO5126766) was selected as a clinical compound. A phase I clinical trial is ongoing for solid cancers.
RESUMEN
Introducing a sulfamide moiety to our coumarin derivatives afforded enhanced Raf/MEK inhibitory activity concomitantly with an acceptable PK profile. Novel sulfamide 17 showed potent HCT116 cell growth inhibition (IC50=8 nM) and good PK profile (bioavailability of 51% in mouse), resulting in high in vivo antitumor efficacy in the HCT116 xenograft (ED50=4.8 mg/kg). We confirmed the sulfamide moiety showed no negative impact on tests run on the compound to evaluate DMPK (PK profiles in three animal species, CYP inhibition and CYP induction) and the safety profile (hERG and AMES tests). Sulfamide 17 had favorable properties that warranted further preclinical assessment.
Asunto(s)
Cumarinas/química , Cumarinas/farmacología , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Quinasas raf/antagonistas & inhibidores , Amidas/química , Amidas/farmacocinética , Amidas/farmacología , Animales , Disponibilidad Biológica , Cumarinas/farmacocinética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Haplorrinos , Ratones , Ratas , Relación Estructura-Actividad , Ácidos Sulfónicos/química , Ácidos Sulfónicos/farmacocinética , Ácidos Sulfónicos/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasas raf/metabolismoRESUMEN
A facile methodology effective in obtaining a set of compounds monofluorinated at various positions (fluorine scan) by chemical synthesis is reported. Direct and nonselective fluorination reactions of our lead compound 1a and key intermediate 2a worked efficiently to afford a total of six monofluorinated derivatives. All of the derivatives kept their physicochemical properties compared with the lead 1a and one of them had enhanced Raf/MEK inhibitory activity. Keeping physicochemical properties could be considered a benefit of monofluorinated derivatives compared with chlorinated derivatives, iodinated derivatives, methylated derivatives, etc. This key finding led to the identification of compound 14d, which had potent tumor growth inhibition in a xenograft model, excellent PK profiles in three animal species, and no critical toxicity.
RESUMEN
A series of benzofuran-based farnesyltransferase inhibitors have been designed and synthesized as antitumor agents. Among them, 11f showed the most potent enzyme inhibitory activity (IC(50)=1.1nM) and antitumor activity in human cancer xenografts in mice.
Asunto(s)
Antineoplásicos/síntesis química , Benzofuranos/síntesis química , Química Farmacéutica/métodos , Farnesiltransferasa/antagonistas & inhibidores , Quinolonas/síntesis química , Animales , Antineoplásicos/farmacología , Benzofuranos/farmacología , Cristalografía por Rayos X , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa/química , Humanos , Concentración 50 Inhibidora , Ratones , Trasplante de Neoplasias , Quinolonas/farmacología , Relación Estructura-ActividadRESUMEN
1,3-beta-D-Glucan synthase, which synthesizes a main component of fungal cell wall, is one of the promising targets for antifungal agents. In order to identify novel chemical classes of 1,3-beta-D-glucan synthase inhibitors, we screened a chemical library monitoring inhibition of the Candida albicans 1,3-beta-D-glucan synthase activity. The piperazine propanol derivative GSI578 [(2,6-difluoro-phenyl)-carbamic acid 3-(4-benzothiazol-2-yl-piperazine-1-yl)-propyl ester] was identified as a potent inhibitor against 1,3-beta-D-glucan synthase with an IC50 value of 0.16 microM. GSI578 exhibited in vitro antifungal activity against pathogenic fungi including C. albicans and Aspergillus fumigatus. Temperature-sensitive mutations of the FKS1 gene in the Deltafks2 background of Saccharomyces cerevisiae, where FKS1 and FKS2 encode putative catalytic subunits of 1,3-beta-D-glucan synthase, altered sensitivity to GSI578. This suggests that the antifungal activity of the piperazine propanol derivative has an effect on 1,3-beta-D-glucan synthase inhibition. Results of our initial evaluation suggest that the piperazine propanol derivative is a novel chemical structure of the class of antifungals which inhibit fungal cell growth by inhibiting fungal 1,3-beta-D-glucan synthase.
Asunto(s)
Antifúngicos/farmacología , Inhibidores Enzimáticos/farmacología , Ésteres/farmacología , Glucosiltransferasas/antagonistas & inhibidores , Piperazinas/farmacología , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/enzimología , Antifúngicos/síntesis química , Aspergillus fumigatus/efectos de los fármacos , Aspergillus fumigatus/crecimiento & desarrollo , Benzotiazoles , Candida albicans/efectos de los fármacos , Candida albicans/crecimiento & desarrollo , Candida glabrata/efectos de los fármacos , Candida glabrata/crecimiento & desarrollo , Equinocandinas , Glucosiltransferasas/genética , Glucosiltransferasas/aislamiento & purificación , Proteínas de la Membrana/genética , Pruebas de Sensibilidad Microbiana , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , TemperaturaRESUMEN
A highly potent water soluble triazole antifungal prodrug, RO0098557 (1), has been identified from its parent, the novel antifungal agent RO0094815 (2). The prodrug includes a triazolium salt linked to an aminocarboxyl moiety, which undergoes enzymatic activation followed by spontaneous chemical degradation to release 2. Prodrug 1 showed high chemical stability and water solubility and exhibited strong antifungal activity against systemic candidiasis and aspergillosis as well as pulmonary aspergillosis in rats.