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1.
Bioorg Med Chem Lett ; 29(6): 815-820, 2019 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-30704812

RESUMEN

The voltage-gated sodium channel, Nav1.1, is predominantly expressed in parvalbumin-positive fast spiking interneurons and has been genetically linked to Dravet syndrome. Starting from a high throughput screening hit isoxazole derivative 5, modifications of 5 via combinations of IonWorks and Q-patch assays successfully identified the nicotinamide derivative 4. Its increasing decay time constant (tau) of Nav1.1 currents at 0.03 µM along with significant selectivity against Nav1.2, Nav1.5, and Nav1.6 and acceptable brain exposure in mice was observed. Compound 4 is a promising Nav1.1 activator that can be used to analyze pathophysiological functions of the Nav1.1 channel towards treating various central nervous system diseases.


Asunto(s)
Descubrimiento de Drogas , Niacinamida/análogos & derivados , Niacinamida/farmacología , Pirrolidinas/farmacología , Agonistas del Canal de Sodio Activado por Voltaje/farmacología , Animales , Barrera Hematoencefálica/metabolismo , Células CHO , Cricetulus , Ratones , Estructura Molecular , Canal de Sodio Activado por Voltaje NAV1.1/metabolismo , Niacinamida/síntesis química , Pirrolidinas/síntesis química , Pirrolidinas/química , Relación Estructura-Actividad , Agonistas del Canal de Sodio Activado por Voltaje/síntesis química , Agonistas del Canal de Sodio Activado por Voltaje/química
2.
Bioorg Med Chem ; 25(14): 3658-3670, 2017 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-28533114

RESUMEN

In order to increase the success rate for developing new Cdc7 inhibitors for cancer therapy, we explored a new chemotype which can comply with the previously-constructed pharmacophore model. Substitution of a pyridine ring of a serendipitously-identified Cdc7 inhibitor 2b with a 3-methylpyrazole resulted in a 4-fold increase in potency and acceptable kinase selectivity, leading to the identification of thieno[3,2-d]pyrimidin-4(3H)-one as an alternative scaffold. Structure-activity relationship (SAR) study revealed that incorporation of a substituted aminomethyl group into the 2-position improved kinase selectivity. Indeed, a pyrrolidinylmethyl derivative 10c was a potent Cdc7 inhibitor (IC50=0.70nM) with high selectivity (Cdk2/Cdc7≥14,000, ROCK1/Cdc7=200). It should be noted that 10c exhibited significant time-dependent Cdc7 inhibition with slow dissociation kinetics, cellular pharmacodynamic (PD) effects, and COLO205 growth inhibition. Additionally, molecular basis of high kinase selectivity of 10c is discussed by using the protein structures of Cdc7 and Cdk2.


Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazoles/química , Pirimidinonas/química , Tiofenos/síntesis química , Sitios de Unión , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/metabolismo , Humanos , Concentración 50 Inhibidora , Cinética , Simulación del Acoplamiento Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Pirimidinonas/síntesis química , Pirimidinonas/farmacocinética , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacocinética , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/genética , Quinasas Asociadas a rho/metabolismo
3.
Bioorg Med Chem ; 25(7): 2133-2147, 2017 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-28284870

RESUMEN

Cell division cycle 7 (Cdc7) is a serine/threonine kinase that plays important roles in the regulation of DNA replication process. A genetic study indicates that Cdc7 inhibition can induce selective tumor-cell death in a p53-dependent manner, suggesting that Cdc7 is an attractive target for the treatment of cancers. In order to identify a new class of potent Cdc7 inhibitors, we generated a putative pharmacophore model based on in silico docking analysis of a known inhibitor with Cdc7 homology model. The pharmacophore model provided a minimum structural motif of Cdc7 inhibitor, by which preliminary medicinal chemistry efforts identified a dihydrothieno[3,2-d]-pyrimidin-4(1H)-one scaffold having a heteroaromatic hinge-binding moiety. The structure-activity relationship (SAR) studies resulted in the discovery of new, potent, and selective Cdc7 inhibitors 14a, c, e. Furthermore, the high selectivity of 14c, e for Cdc7 over Rho-associated protein kinase 1 (ROCK1) is discussed by utilizing a docking study with Cdc7 and ROCK2 crystal structures.


Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinonas/farmacología , Humanos , Modelos Moleculares , Pirimidinonas/síntesis química , Pirimidinonas/química , Relación Estructura-Actividad
4.
Bioorg Med Chem ; 25(14): 3768-3779, 2017 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-28571972

RESUMEN

A lead compound A was identified previously as an stearoyl coenzyme A desaturase (SCD) inhibitor during research on potential treatments for obesity. This compound showed high SCD1 binding affinity, but a poor pharmacokinetic (PK) profile and limited chemical accessibility, making it suboptimal for use in anticancer research. To identify potent SCD1 inhibitors with more promising PK profiles, we newly designed a series of 'non-spiro' 4, 4-disubstituted piperidine derivatives based on molecular modeling studies. As a result, we discovered compound 1a, which retained moderate SCD1 binding affinity. Optimization around 1a was accelerated by analyzing Hansch-Fujita and Hammett constants to obtain 4-phenyl-4-(trifluoromethyl)piperidine derivative 1n. Fine-tuning of the azole moiety of 1n led to compound 1o (T-3764518), which retained nanomolar affinity and exhibited an excellent PK profile. Reflecting the good potency and PK profile, orally administrated compound 1o showed significant pharmacodynamic (PD) marker reduction (at 0.3mg/kg, bid) in HCT116 mouse xenograft model and tumor growth suppression (at 1mg/kg, bid) in 786-O mouse xenograft model. In conclusion, we identified a new series of SCD1 inhibitors, represented by compound 1o, which represents a promising new chemical tool suitable for the study of SCD1 biology as well as the potential development of novel anticancer therapies.


Asunto(s)
Antineoplásicos/química , Inhibidores Enzimáticos/síntesis química , Oxadiazoles/síntesis química , Piridazinas/síntesis química , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Células HCT116 , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Microsomas Hepáticos/metabolismo , Oxadiazoles/farmacocinética , Oxadiazoles/uso terapéutico , Oxadiazoles/toxicidad , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacología , Unión Proteica , Piridazinas/farmacocinética , Piridazinas/uso terapéutico , Piridazinas/toxicidad , Compuestos de Espiro/química , Estearoil-CoA Desaturasa/metabolismo , Relación Estructura-Actividad , Trasplante Heterólogo
5.
J Med Invest ; 70(3.4): 403-410, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37940524

RESUMEN

X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder associated with peroxisomal dysfunction. Patients with this rare disease accumulate very long-chain fatty acids (VLCFAs) in their bodies because of impairment of peroxisomal VLCFA ?-oxidation. Several clinical types of X-ALD, ranging from mild (axonopathy in the spinal cord) to severe (cerebral demyelination), are known. However, the molecular basis for this phenotypic variability remains largely unknown. In this study, we determined plasma ceramide (CER) profile using liquid chromatography-tandem mass spectrometry. We characterized the molecular species profile of CER in the plasma of patients with mild (adrenomyeloneuropathy;AMN) and severe (cerebral) X-ALD. Eleven X-ALD patients (five cerebral, five AMN, and one carrier) and 10 healthy volunteers participated in this study. Elevation of C26:0 CER was found to be a common feature regardless of the clinical types. The level of C26:1 CER was significantly higher in AMN but not in cerebral type, than that in healthy controls. The C26:1 CER level in the cerebral type was significantly lower than that in the AMN type. These results suggest that a high level of C26:0 CER, along with a control level of C26:1 CER, is a characteristic feature of the cerebral type X-ALD. J. Med. Invest. 70 : 403-410, August, 2023.


Asunto(s)
Adrenoleucodistrofia , Ceramidas , Humanos , Adrenoleucodistrofia/genética , Ceramidas/sangre
6.
Bioorg Med Chem ; 20(15): 4680-92, 2012 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-22763369

RESUMEN

As an alternative to the previously reported solid dispersion formulation for enhancing the oral absorption of thiazolo[5,4-b]pyridine 1, we investigated novel N-acyl imide prodrugs of 1 as RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors. Introducing N-acyl promoieties at the benzanilide position gave chemically stable imides. N-tert-Butoxycarbonyl (Boc) introduced imide 6 was a promising prodrug, which was converted to the active compound 1 after its oral administration in mice. Cocrystals of 6 with AcOH (6b) possessed good physicochemical properties with moderate thermodynamic solubility (19µg/mL). This crystalline prodrug 6b was rapidly and enzymatically converted into 1 after its oral absorption in mice, rats, dogs, and monkeys. Prodrug 6b showed in vivo antitumor regressive efficacy (T/C=-6.4%) in an A375 melanoma xenograft model in rats. Hence, we selected 6b as a promising candidate and are performing further studies. Herein, we report the design, synthesis, and characterization of novel imide-type prodrugs.


Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Imidas/farmacología , Profármacos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/síntesis química , Línea Celular Tumoral , Cristalografía por Rayos X , Perros , Relación Dosis-Respuesta a Droga , Femenino , Haplorrinos , Humanos , Imidas/administración & dosificación , Imidas/síntesis química , Ratones , Modelos Moleculares , Estructura Molecular , Profármacos/administración & dosificación , Profármacos/síntesis química , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/síntesis química , Ratas , Ratas Desnudas , Solubilidad , Relación Estructura-Actividad , Termodinámica , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Bioorg Med Chem ; 20(18): 5600-15, 2012 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-22883026

RESUMEN

Our aim was to discover RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors that possess strong activity and sufficient oral absorption, and thus, we selected a 5-amino-linked thiazolo[5,4-d]pyrimidine derivative as the lead compound because of its potential kinase inhibitory activities and its desired solubility. The novel tertiary 1-cyano-1-methylethoxy substituent was designed to occupy the hydrophobic region of 'back pocket' of BRAF on the basis of the X-ray co-crystal structure data of BRAF. In addition, we found that N-methylation of the amine linker could control the twisted molecular conformation leading to improved solubility. These approaches produced N-methyl thiazolo[5,4-b]pyridine-5-amine derivative 5. To maximize the in vivo efficacy, we attempted salt formation of 5. Our result indicated that the besylate monohydrate salt form (5c) showed significant improvement of both solubility and oral absorption. Owing to the improved physicochemical properties, compound 5c demonstrated regressive antitumor efficacy in a HT-29 xenograft model.


Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Neoplasias Experimentales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Tiazoles/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Células HT29 , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Ratones , Microsomas/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Ratas , Ratas Endogámicas F344 , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
9.
PLoS One ; 15(10): e0240718, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33064779

RESUMEN

Emerging evidence indicates that alternative splicing plays a critical role in cancer progression through abnormal expression or mutation of splicing factors. Small-molecule splicing modulators have recently attracted considerable attention as a novel class of cancer therapeutics. CDC-like kinases (CLKs) are central to exon recognition in mRNA splicing and CLK inhibitors exhibit anti-tumour activities. Most importantly, molecular mechanism-based combination strategies for cancer therapy must be considered. However, it remains unclear whether CLK inhibitors modulate expression and splicing of apoptosis-related genes, and whether CLK inhibitors enhance cytotoxicity in combination with apoptosis inducers. Here we report an appropriate mechanism-based drug combination approach. Unexpectedly, we found that the CLK inhibitor T3 rapidly induced apoptosis in A2780 cells and G2/M cell cycle arrest in HCT116 cells. Regardless of the different phenotypes of the two cancer cell types, T3 decreased the levels of anti-apoptotic proteins (cIAP1, cIAP2, XIAP, cFLIP and Mcl-1) for a short period of exposure and altered the splicing of the anti-apoptotic MCL1L and CFLAR isoform in A2780 and HCT116 cells. In contrast, other members of the Bcl-2 family (i.e., Bcl-xL and Bcl-2) were resistant to T3-induced expression and splicing modulation. T3 and a Bcl-xL/Bcl-2 inhibitor synergistically induced apoptosis. Taken together, the use of a CLK inhibitor is a novel therapeutic approach to sensitise cancer cells to Bcl-xL/Bcl-2 inhibitors.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Empalme Alternativo/efectos de los fármacos , Antineoplásicos/química , Apoptosis/genética , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Fase G2/efectos de los fármacos , Humanos , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Precursores del ARN/genética , Precursores del ARN/metabolismo
10.
Biochem Biophys Rep ; 21: 100726, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32055714

RESUMEN

Cabozantinib is known as an inhibitor of receptor tyrosine kinases mainly targeting AXL receptor tyrosine kinase (AXL), MET proto-oncogene-encoded receptor tyrosine kinase (MET), and vascular endothelial growth factor receptor 2. Growth arrest-specific 6 (GAS6) and hepatocyte growth factor (HGF), the natural ligands of AXL and MET, respectively, are associated with the induction of cancer cell proliferation or metastasis. Currently, it is still unclear how cabozantinib regulates cancer cell migration and invasion by inhibiting AXL and MET. This study was conducted to investigate the mechanism underlying the anti-cancer effects of cabozantinib through regulation of AXL and MET signaling. The results of Boyden chamber assays showed that cancer cell migration was induced by GAS6 and HGF in SKOV3 cells in serum-free medium. Combinatorial treatment with GAS6 and HGF exerted an additive effect on cell migration. Furthermore, we examined the role of AXL and MET signaling in cell migration. Short interfering RNA targeting AXL and MET inhibited GAS6- and HGF-induced migration, respectively. Double knockdown of AXL and MET completely suppressed cell migration induced by combination treatment with GAS6 and HGF compared to AXL or MET inhibition alone. Finally, we investigated the effects of cabozantinib on cell migration and invasion. Cabozantinib inhibited AXL and MET phosphorylation and downregulated the downstream mediators, phosphorylated SRC in the presence of both GAS6 and HGF in SKOV3 cells. The cell migration and invasion induced by combined GAS6 and HGF treatment were suppressed by cabozantinib, but not by capmatinib, a selective MET inhibitor. Our data indicate that the GAS6-AXL and HGF-MET signal pathways markedly contribute to cancer cell migration and invasion in an independent manner, suggesting that simultaneous inhibition of these two pathways contributes to the anti-cancer effects of cabozantinib.

11.
J Med Chem ; 63(3): 1084-1104, 2020 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-31895562

RESUMEN

In our pursuit of developing a novel, potent, and selective cell division cycle 7 (Cdc7) inhibitor, we optimized the previously reported thieno[3,2-d]pyrimidinone analogue I showing time-dependent Cdc7 kinase inhibition and slow dissociation kinetics. These medicinal chemistry efforts led to the identification of compound 3d, which exhibited potent cellular activity, excellent kinase selectivity, and antitumor efficacy in a COLO205 xenograft mouse model. However, the issue of formaldehyde adduct formation emerged during a detailed study of 3d, which was deemed an obstacle to further development. A structure-based approach to circumvent the adduct formation culminated in the discovery of compound 11b (TAK-931) possessing a quinuclidine moiety as a preclinical candidate. In this paper, the design, synthesis, and biological evaluation of this series of compounds will be presented.


Asunto(s)
Antineoplásicos/uso terapéutico , Proteínas de Ciclo Celular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazolonas/uso terapéutico , Pirimidinas/uso terapéutico , Pirimidinonas/uso terapéutico , Quinuclidinas/uso terapéutico , Tiofenos/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Sitios de Unión , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Diseño de Fármacos , Descubrimiento de Drogas , Formaldehído/química , Humanos , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazolonas/farmacología , Pirimidinas/farmacología , Pirimidinonas/síntesis química , Pirimidinonas/metabolismo , Quinuclidinas/síntesis química , Quinuclidinas/metabolismo , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Sci Adv ; 5(5): eaav3660, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31131319

RESUMEN

Replication stress (RS) is a cancer hallmark; chemotherapeutic drugs targeting RS are widely used as treatments for various cancers. To develop next-generation RS-inducing anticancer drugs, cell division cycle 7 (CDC7) has recently attracted attention as a target. We have developed an oral CDC7-selective inhibitor, TAK-931, as a candidate clinical anticancer drug. TAK-931 induced S phase delay and RS. TAK-931-induced RS caused mitotic aberrations through centrosome dysregulation and chromosome missegregation, resulting in irreversible antiproliferative effects in cancer cells. TAK-931 exhibited significant antiproliferative activity in preclinical animal models. Furthermore, in indication-seeking studies using large-scale cell panel data, TAK-931 exhibited higher antiproliferative activities in RAS-mutant versus RAS-wild-type cells; this finding was confirmed in pancreatic patient-derived xenografts. Comparison analysis of cell panel data also demonstrated a unique efficacy spectrum for TAK-931 compared with currently used chemotherapeutic drugs. Our findings help to elucidate the molecular mechanisms for TAK-931 and identify potential target indications.


Asunto(s)
Antineoplásicos/farmacología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazolonas/farmacología , Pirimidinas/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular , Separación Celular , Supervivencia Celular , Centrosoma/efectos de los fármacos , Aberraciones Cromosómicas/efectos de los fármacos , Biología Computacional , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Células HeLa , Humanos , Concentración 50 Inhibidora , Estimación de Kaplan-Meier , Ratones , Ratones Endogámicos BALB C , Mitosis/efectos de los fármacos , Modelos Animales , Mutación , Trasplante de Neoplasias , Neoplasias Pancreáticas/tratamiento farmacológico , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacología , Proteómica , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Org Lett ; 10(12): 2369-72, 2008 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-18498172

RESUMEN

An improved synthesis of the indole unit, a key intermediate for eudistomin C, was established utilizing Makosza's indole synthesis. A concise total synthesis of eudistomin E was achieved on the basis of the improved synthesis.


Asunto(s)
Carbolinas/síntesis química , Indoles/síntesis química , Animales , Indoles/química , Estructura Molecular , Urocordados/química
14.
Org Lett ; 9(23): 4737-40, 2007 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-17935340

RESUMEN

A synthetic route to vinblastine and its analogues with an ethynyl group, which features a stereoselective coupling of an 11-membered key intermediate with vindoline, is described. Transformations of the alkynyl moiety including a partial reduction as well as a Sonogashira coupling furnished a variety of analogues.


Asunto(s)
Vinblastina/análogos & derivados , Vinblastina/síntesis química , Proliferación Celular/efectos de los fármacos , Humanos , Células K562 , Estructura Molecular , Vinblastina/química , Vinblastina/toxicidad
15.
Nat Commun ; 8(1): 7, 2017 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-28232751

RESUMEN

CDC-like kinase phosphorylation of serine/arginine-rich proteins is central to RNA splicing reactions. Yet, the genomic network of CDC-like kinase-dependent RNA processing events remains poorly defined. Here, we explore the connectivity of genomic CDC-like kinase splicing functions by applying graduated, short-exposure, pharmacological CDC-like kinase inhibition using a novel small molecule (T3) with very high potency, selectivity, and cell-based stability. Using RNA-Seq, we define CDC-like kinase-responsive alternative splicing events, the large majority of which monotonically increase or decrease with increasing CDC-like kinase inhibition. We show that distinct RNA-binding motifs are associated with T3 response in skipped exons. Unexpectedly, we observe dose-dependent conjoined gene transcription, which is associated with motif enrichment in the last and second exons of upstream and downstream partners, respectively. siRNA knockdown of CLK2-associated genes significantly increases conjoined gene formation. Collectively, our results reveal an unexpected role for CDC-like kinase in conjoined gene formation, via regulation of 3'-end processing and associated splicing factors.The phosphorylation of serine/arginine-rich proteins by CDC-like kinase is a central regulatory mechanism for RNA splicing reactions. Here, the authors synthesize a novel small molecule CLK inhibitor and map CLK-responsive alternative splicing events and discover an effect on conjoined gene transcription.


Asunto(s)
Empalme Alternativo/efectos de los fármacos , Imidazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Pirimidinas/farmacología , ARN Mensajero/genética , Proteínas de Unión al ARN/genética , Exones , Perfilación de la Expresión Génica , Genoma Humano , Células HCT116 , Humanos , Imidazoles/síntesis química , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Pirimidinas/síntesis química , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Proteínas de Unión al ARN/antagonistas & inhibidores , Proteínas de Unión al ARN/metabolismo , Relación Estructura-Actividad , Transcripción Genética
16.
J Med Chem ; 55(7): 3452-78, 2012 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-22376051

RESUMEN

To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity.


Asunto(s)
Antineoplásicos/síntesis química , Benzamidas/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Tiazoles/síntesis química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Benzamidas/farmacocinética , Benzamidas/farmacología , Benzoatos/síntesis química , Benzoatos/farmacocinética , Benzoatos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Imidazoles/síntesis química , Imidazoles/farmacocinética , Imidazoles/farmacología , Ratones , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Modelos Moleculares , Estructura Molecular , Fosforilación , Piridazinas/síntesis química , Piridazinas/farmacocinética , Piridazinas/farmacología , Ratas , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Ann Allergy Asthma Immunol ; 93(1): 98-100, 2004 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15281478

RESUMEN

BACKGROUND: Wheat is a food allergen that occasionally causes a systemic allergic reaction; however, little is known about the quantities of wheat allergen required to evoke allergic symptoms. OBJECTIVE: To report the case of a wheat allergic boy who experienced systemic urticaria and angioedema within 40 minutes after the ingestion of 9 g of packed rice crackers. METHODS: A skin prick test and IgE immunoblotting with wheat proteins were performed. Contamination of wheat protein in the offending rice cracker and other processed rice crackers from local food retail outlets, with labels that did not mention wheat, was examined with enzyme-linked immunosorbent assaying. RESULTS: A skin reaction to wheat was positive. IgE-bound bands were observed with water- and salt-soluble wheat protein and ethanol-soluble wheat gliadin in immunoblotting. A trace quantity of wheat protein, 1.50 microg/g, was determined in the offending rice cracker. In addition, 3 of 8 other kinds of processed rice crackers were contaminated by wheat protein, with levels ranging from 0.26 to 1.13 microg/g. CONCLUSIONS: Approximately 13.5 microg of wheat protein can elicit a systemic adverse reaction in highly sensitive, wheat allergic individuals. The present study confirms the need for control of contamination of food by nondeclared proteins.


Asunto(s)
Urticaria/etiología , Hipersensibilidad al Trigo/complicaciones , Contaminación de Alimentos , Humanos , Inmunoglobulina E/sangre , Lactante , Masculino , Pruebas Cutáneas
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