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1.
BMC Med ; 20(1): 470, 2022 12 08.
Artículo en Inglés | MEDLINE | ID: mdl-36482371

RESUMEN

BACKGROUND: The recruitment of a sufficient number of immune cells to induce an inflamed tumor microenvironment (TME) is a prerequisite for effective response to cancer immunotherapy. The immunological phenotypes in the TME of EGFR-mutated lung cancer were characterized as non-inflamed, for which immunotherapy is largely ineffective. METHODS: Global proteomic and phosphoproteomic data from lung cancer tissues were analyzed aiming to map proteins related to non-inflamed TME. The ex vivo and in vivo studies were carried out to evaluate the anti-tumor effect. Proteomics was applied to identify the potential target and signaling pathways. CRISPR-Cas9 was used to knock out target genes. The changes of immune cells were monitored by flow cytometry. The correlation between PKCδ and PD-L1 was verified by clinical samples. RESULTS: We proposed that PKCδ, a gatekeeper of immune homeostasis with kinase activity, is responsible for the un-inflamed phenotype in EGFR-mutated lung tumors. It promotes tumor progression by stimulating extracellular matrix (ECM) and PD-L1 expression which leads to immune exclusion and assists cancer cell escape from T cell surveillance. Ablation of PKCδ enhances the intratumoral penetration of T cells and suppresses the growth of tumors. Furthermore, blocking PKCδ significantly sensitizes the tumor to immune checkpoint blockade (ICB) therapy (αPD-1) in vitro and in vivo model. CONCLUSIONS: These findings revealed that PKCδ is a critical switch to induce inflamed tumors and consequently enhances the efficacy of ICB therapy in EGFR-mutated lung cancer. This opens a new avenue for applying immunotherapy against recalcitrant tumors.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Proteína Quinasa C-delta , Humanos , Antígeno B7-H1/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Proteómica , Microambiente Tumoral , Proteína Quinasa C-delta/genética
2.
Int J Mol Sci ; 23(17)2022 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-36077054

RESUMEN

A-to-I RNA editing and m6A modification are two of the most prevalent types of RNA modifications controlling gene expression in mammals and play very important roles in tumorigenesis and tumor progression. However, the functional roles and correlations of these two RNA modifications remain to be further investigated in cancer. Herein, we show that ADAR1, an A-to-I RNA-editing enzyme, interacts with METTL3 and increases its protein level to promote the proliferation, migration and invasion of breast cancer cells through a mechanism connecting ADAR1, METTL3 and YTHDF1. We show that both ADAR1 and METTL3 are upregulated in breast cancer samples, and ADAR1 positively correlates with METTL3; ADAR1 edits METTL3 mRNA and changes its binding site to miR532-5p, leading to increased METTL3 protein, which further targets ARHGAP5, recognized by YTHDF1. Additionally, we show that loss of ADAR1 significantly inhibits breast cancer growth in vivo. Collectively, our findings identify the ADAR1-METTL3 axis as a novel, important pathway that connects A-to-I editing and m6A RNA modifications during breast cancer progression.


Asunto(s)
Adenosina Desaminasa/metabolismo , Neoplasias de la Mama , Metiltransferasas/metabolismo , MicroARNs , Proteínas de Unión al ARN/metabolismo , Adenosina Desaminasa/genética , Neoplasias de la Mama/genética , Femenino , Proteínas Activadoras de GTPasa/metabolismo , Humanos , MicroARNs/genética , Edición de ARN , ARN Mensajero/genética , Proteínas de Unión al ARN/genética
3.
Drug Dev Res ; 82(1): 133-142, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32931039

RESUMEN

Cancers resist targeted therapeutics by drug-escape signaling. Multitarget drugs co-targeting cancer and drug-escape mediators (DEMs) are clinically advantageous. DEM coverage may be expanded by drug combinations. This work evaluated to what extent the kinase DEMs (KDEMs) can be optimally co-targeted by drug combinations based on target promiscuities of individual drugs. We focused on 41 approved and 28 clinical trial small molecule kinase inhibitor drugs with available experimental kinome and clinical pharmacokinetic data. From the kinome inhibitory profiles of these drugs, drug combinations were assembled for optimally co-targeting an established cancer target (EGFR, HER2, ABL1, or MEK1) and 9-16 target-associated KDEMs at comparable potency levels as that against the cancer target. Each set of two-, three-, and four-drug combinations co-target 36-71%, 44-89%, 50-88%, and 27-55% KDEMs of EGFR, HER2, ABL1, and MEK1, respectively, compared with the 36, 33, 38, and 18% KDEMs maximally co-targeted by an existing drug or drug combination approved or clinically tested for the respective cancer. Some co-targeted KDEMs are not covered by any existing drug or drug combination. Our work suggested that novel drug combinations may be constructed for optimally co-targeting cancer and drug escape by the exploitation of drug target promiscuities.


Asunto(s)
Antineoplásicos/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Antineoplásicos/farmacocinética , Combinación de Medicamentos , Sistemas de Liberación de Medicamentos , Resistencia a Antineoplásicos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Quinasas/metabolismo
4.
Bioorg Med Chem Lett ; 30(6): 126966, 2020 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-32001136

RESUMEN

Herein, we report the discovery of a series of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as a new class of ROCK inhibitors. Structure-activity relationship studies of these compounds led to the identification of the most potent compound, 3-(3-methoxybenzyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)thieno[2,3-d]pyrimidin-4(3H)-one (8k), which showed IC50 values of 0.004 µM and 0.001 µM against ROCK Ⅰ and ROCK Ⅱ, respectively. In vitro, 8k significantly reduced the phosphorylation level of ROCK downstream signaling protein and induce changes in cell morphology and migration. Overall, this study provides a promising lead compound for drug discovery targeting ROCKs.


Asunto(s)
Inhibidores de Proteínas Quinasas/química , Pirimidinonas/química , Quinasas Asociadas a rho/antagonistas & inhibidores , Movimiento Celular/efectos de los fármacos , Descubrimiento de Drogas , Humanos , Fosforilación , Inhibidores de Proteínas Quinasas/metabolismo , Pirimidinonas/metabolismo , Relación Estructura-Actividad
5.
Drug Dev Res ; 80(2): 246-252, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30422335

RESUMEN

The clinical advantage of co-targeting cancer drug escape has been indicated by the percentage of these co-targeting drugs among all multi-target drugs in clinics and clinical trials. This clinical advantage needs to be further interrogated from such perspectives as the clinical impact of multi-target inhibition of drug-escape mediators. This impact may be reflected by drug sales data, that is, multi-target inhibition of higher number of drug-escape mediators favors the expanded coverage of drug-resistant patients leading to higher sales. We investigated whether this expectation is followed by the 25 FDA-approved anticancer kinase inhibitors, which were divided into 11 groups of comparable therapeutic mechanisms and approval years. We found 19 (76%) drugs to follow and 3 (12%) drugs not to follow this expectation. The remaining two (8%) and one (4%) drugs cannot be assessed due to insufficient data and incomparability. Therefore, drug sales strongly indicate the clinical advantage of multi-target inhibition of cancer drug escapes.


Asunto(s)
Antineoplásicos/economía , Resistencia a Antineoplásicos , Terapia Molecular Dirigida , Neoplasias/economía , Inhibidores de Proteínas Quinasas/economía , Antineoplásicos/uso terapéutico , Comercio , Aprobación de Drogas , Humanos , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del Tratamiento , Estados Unidos , United States Food and Drug Administration
6.
Bioinformatics ; 33(20): 3276-3282, 2017 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-28549078

RESUMEN

MOTIVATION: Genetic and gene expression variations within and between populations and across geographical regions have substantial effects on the biological phenotypes, diseases, and therapeutic response. The development of precision medicines can be facilitated by the OMICS studies of the patients of specific ethnicity and geographic region. However, there is an inadequate facility for broadly and conveniently accessing the ethnic and regional specific OMICS data. RESULTS: Here, we introduced a new free database, HEROD, a human ethnic and regional specific OMICS database. Its first version contains the gene expression data of 53 070 patients of 169 diseases in seven ethnic populations from 193 cities/regions in 49 nations curated from the Gene Expression Omnibus (GEO), the ArrayExpress Archive of Functional Genomics Data (ArrayExpress), the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). Geographic region information of curated patients was mainly manually extracted from referenced publications of each original study. These data can be accessed and downloaded via keyword search, World map search, and menu-bar search of disease name, the international classification of disease code, geographical region, location of sample collection, ethnic population, gender, age, sample source organ, patient type (patient or healthy), sample type (disease or normal tissue) and assay type on the web interface. AVAILABILITY AND IMPLEMENTATION: The HEROD database is freely accessible at http://bidd2.nus.edu.sg/herod/index.php. The database and web interface are implemented in MySQL, PHP and HTML with all major browsers supported. CONTACT: phacyz@nus.edu.sg.


Asunto(s)
Biología Computacional/métodos , Bases de Datos Genéticas , Variación Genética , Genoma Humano , Grupos de Población/genética , Transcriptoma , Predisposición Genética a la Enfermedad , Humanos , Internet , Neoplasias/genética
7.
Int J Mol Sci ; 19(6)2018 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-29843366

RESUMEN

Human lung cancer H1299 (p53-null) cells often display enhanced susceptibility to chemotherapeutics comparing to A549 (p53-wt) cells. However, little is known regarding to the association of DNA damage-response (DDR) pathway heterogeneity with drug sensitivity in these two cells. We investigated the DDR pathway differences between A549 and H1299 cells exposed to 8-chloro-adenosine (8-Cl-Ado), a potential anticancer drug that can induce DNA double-strand breaks (DSBs), and found that the hypersensitivity of H1299 cells to 8-Cl-Ado is associated with its DSB overaccumulation. The major causes of excessive DSBs in H1299 cells are as follows: First, defect of p53-p21 signal and phosphorylation of SMC1 increase S phase cells, where replication of DNA containing single-strand DNA break (SSB) produces more DSBs in H1299 cells. Second, p53 defect and no available induction of DNA repair protein p53R2 impair DNA repair activity in H1299 cells more severely than A549 cells. Third, cleavage of PARP-1 inhibits topoisomerase I and/or topoisomerase I-like activity of PARP-1, aggravates DNA DSBs and DNA repair mechanism impairment in H1299 cells. Together, DDR pathway heterogeneity of cancer cells is linked to cancer susceptibility to DNA damage-based chemotherapeutics, which may provide aid in design of chemotherapy strategy to improve treatment outcomes.


Asunto(s)
2-Cloroadenosina/análogos & derivados , Antineoplásicos/farmacología , Roturas del ADN de Doble Cadena/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , ADN de Neoplasias/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , 2-Cloroadenosina/farmacología , Células A549 , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Replicación del ADN , ADN-Topoisomerasas de Tipo I/genética , ADN-Topoisomerasas de Tipo I/metabolismo , ADN de Neoplasias/metabolismo , Humanos , Especificidad de Órganos , Fosforilación , Poli(ADP-Ribosa) Polimerasa-1/genética , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Transducción de Señal , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
8.
Bioorg Med Chem Lett ; 27(14): 3201-3204, 2017 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-28539219

RESUMEN

Herein we report the discovery of a series of new small molecule inhibitors of histone lysine demethylase 4D (KDM4D). Molecular docking was first performed to screen for new KDM4D inhibitors from various chemical databases. Two hit compounds were retrieved. Further structural optimization and structure-activity relationship (SAR) analysis were carried out to the more selective one, compound 2, which led to the discovery of several new KDM4D inhibitors. Among them, compound 10r is the most potent one with an IC50 value of 0.41±0.03µM against KDM4D. Overall, compound 10r could be taken as a good lead compound for further studies.


Asunto(s)
Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Nitrilos/química , Pirazoles/química , Pirimidinas/química , Sitios de Unión , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Histona Demetilasas con Dominio de Jumonji/metabolismo , Simulación del Acoplamiento Molecular , Nitrilos/síntesis química , Nitrilos/metabolismo , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Estructura Terciaria de Proteína , Relación Estructura-Actividad
9.
J Chem Inf Model ; 57(7): 1640-1651, 2017 07 24.
Artículo en Inglés | MEDLINE | ID: mdl-28661143

RESUMEN

Small-molecule target identification is an important and challenging task for chemical biology and drug discovery. Structure-based virtual target identification has been widely used, which infers and prioritizes potential protein targets for the molecule of interest (MOI) principally via a scoring function. However, current "universal" scoring functions may not always accurately identify targets to which the MOI binds from the retrieved target database, in part due to a lack of consideration of the important binding features for an individual target. Here, we present IFPTarget, a customized virtual target identification method, which uses an interaction fingerprinting (IFP) method for target-specific interaction analyses and a comprehensive index (Cvalue) for target ranking. Evaluation results indicate that the IFP method enables substantially improved binding pose prediction, and Cvalue has an excellent performance in target ranking for the test set. When applied to screen against our established target library that contains 11,863 protein structures covering 2842 unique targets, IFPTarget could retrieve known targets within the top-ranked list and identified new potential targets for chemically diverse drugs. IFPTarget prediction led to the identification of the metallo-ß-lactamase VIM-2 as a target for quercetin as validated by enzymatic inhibition assays. This study provides a new in silico target identification tool and will aid future efforts to develop new target-customized methods for target identification.


Asunto(s)
Modelos Moleculares , Proteínas/metabolismo , Secuencia de Aminoácidos , Sitios de Unión , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Unión Proteica , Conformación Proteica , Proteínas/química , Especificidad por Sustrato , beta-Lactamasas/química , beta-Lactamasas/metabolismo
10.
Nucleic Acids Res ; 43(Database issue): D558-65, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25414339

RESUMEN

Similarity-based clustering and classification of compounds enable the search of drug leads and the structural and chemogenomic studies for facilitating chemical, biomedical, agricultural, material and other industrial applications. A database that organizes compounds into similarity-based as well as scaffold-based and property-based families is useful for facilitating these tasks. CFam Chemical Family database http://bidd2.cse.nus.edu.sg/cfam was developed to hierarchically cluster drugs, bioactive molecules, human metabolites, natural products, patented agents and other molecules into functional families, superfamilies and classes of structurally similar compounds based on the literature-reported high, intermediate and remote similarity measures. The compounds were represented by molecular fingerprint and molecular similarity was measured by Tanimoto coefficient. The functional seeds of CFam families were from hierarchically clustered drugs, bioactive molecules, human metabolites, natural products, patented agents, respectively, which were used to characterize families and cluster compounds into families, superfamilies and classes. CFam currently contains 11,643 classes, 34,880 superfamilies and 87,136 families of 490,279 compounds (1691 approved drugs, 1228 clinical trial drugs, 12,386 investigative drugs, 262,881 highly active molecules, 15,055 human metabolites, 80,255 ZINC-processed natural products and 116,783 patented agents). Efforts will be made to further expand CFam database and add more functional categories and families based on other types of molecular representations.


Asunto(s)
Bases de Datos de Compuestos Químicos , Descubrimiento de Drogas , Productos Biológicos/clasificación , Análisis por Conglomerados , Humanos , Internet , Preparaciones Farmacéuticas/clasificación
11.
Chemistry ; 22(31): 10969-75, 2016 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-27362319

RESUMEN

P450 119 peroxygenase and its site-directed mutants are discovered to catalyze the enantioselective epoxidation of methyl-substituted styrenes. Two new site-directed P450 119 mutants, namely T213Y and T213M, which were designed to improve the enantioselectivity and activity for the epoxidation of styrene and its methyl substituted derivatives, were studied. The T213M mutant is found to be the first engineered P450 peroxygenase that shows highly enantioselective epoxidation of cis-ß-methylstyrenes, with up to 91 % ee. Molecular modeling studies provide insights into the different catalytic activity of the T213M mutant and the T213Y mutant in the epoxidation of cis-ß-methylstyrene. The results of the calculations also contribute to a better understanding of the substrate specificity and configuration control for the regio- and stereoselective peroxygenation catalyzed by the T213M mutant.


Asunto(s)
Compuestos Epoxi/química , Oxigenasas de Función Mixta/química , Ingeniería de Proteínas/métodos , Estireno/química , Catálisis , Modelos Moleculares , Estereoisomerismo
12.
Bioorg Med Chem Lett ; 26(18): 4552-4557, 2016 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-27524309

RESUMEN

Lysine specific demethylase 1 (LSD1) plays an important role in regulating histone lysine methylation at residues K4 and K9 on histone H3 and is recognized as an attractive therapeutic target in multiple malignancies. In this study, a series of novel (E)-N'-(2,3-dihydro-1H-inden-1-ylidene) benzohydrazides were synthesized and biologically evaluated for their potential LSD1 inhibitory effect. Among them, compounds 5a and 5n showed the most potent LSD1 inhibitory activity with IC50 values of 1.4 and 1.7nM, respectively, which were about 10 times more potent compared with (E)-N-(1-(5-chloro-2-hydroxyphenyl) ethylidene)-3-(morpholinosulf-only) benzohydrazide (J. Med. Chem.2013, 56, 9496-9508; as reference compound). Compounds 5a and 5n also exhibited marked anti-proliferation activities against cancer cell lines that highly expressed LSD1. These results suggest that these optimized compounds might be served as promising LSD1 inhibitors against cancer, which merit further study.


Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Histona Demetilasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Enlace de Hidrógeno , Conformación Molecular , Relación Estructura-Actividad
13.
Bioorg Med Chem Lett ; 26(9): 2284-8, 2016 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-27020306

RESUMEN

Herein we report the discovery of a series of new KDM5A inhibitors. A three-dimensional (3D) structure model of KDM5A jumonji domain was firstly established based on homology modeling. Molecular docking-based virtual screening was then performed against commercial chemical databases. A number of hit compounds were retrieved. Further structural optimization and structure-activity relationship (SAR) analysis were carried out to the most active hit compound, 9 (IC50: 2.3 µM), which led to the discovery of several new KDM5A inhibitors. Among them, compound 15e is the most potent one with an IC50 value of 0.22 µM against KDM5A. This compound showed good selectivity for KDM5A and considerable ability to suppress the demethylation of H3K4me3 in intact cells. Compound 15e could be taken as a good lead compound for further studies.


Asunto(s)
Proteína 2 de Unión a Retinoblastoma/antagonistas & inhibidores , Descubrimiento de Drogas , Humanos , Relación Estructura-Actividad
14.
Bioorg Med Chem ; 24(4): 827-34, 2016 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-26774253

RESUMEN

The development of amyloid-specific fluorophores allows the visualization of cerebral ß-amyloid deposits using optical imaging technology. In the present study, a series of smart styrylpyran fluorophores with compact donor-acceptor architecture were designed and evaluated for noninvasive detection of cerebral ß-amyloid deposits. Spectral behavior of the fluorophores changed significantly (optical turn-on) upon binding to ß-amyloid aggregates. Computational studies were conducted to correlate the experimental Kd values with calculated binding energies, speculating the relationship between fluorophore structure and ß-amyloid affinity. In vivo studies demonstrated that PAD-2 could discriminate APP/PS1 transgenic mice from wild type controls, with specific labeling of cerebral ß-amyloid deposits confirmed by ex vivo observation. Collectively, these styrylpyran fluorophores could provide a new scaffold for the development of optical imaging probes targeting cerebral ß-amyloid deposits.


Asunto(s)
Enfermedad de Alzheimer/patología , Amiloide/ultraestructura , Colorantes Fluorescentes/síntesis química , Placa Amiloide/patología , Piranos/síntesis química , Estirenos/síntesis química , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/metabolismo , Secuencias de Aminoácidos , Amiloide/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/ultraestructura , Modelos Animales de Enfermedad , Colorantes Fluorescentes/administración & dosificación , Colorantes Fluorescentes/metabolismo , Masculino , Ratones , Ratones Transgénicos , Simulación del Acoplamiento Molecular , Datos de Secuencia Molecular , Imagen Óptica , Placa Amiloide/diagnóstico , Placa Amiloide/metabolismo , Unión Proteica , Estructura Secundaria de Proteína , Piranos/administración & dosificación , Piranos/metabolismo , Relación Estructura-Actividad , Estirenos/administración & dosificación , Estirenos/metabolismo
15.
Methods ; 71: 158-66, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25462557

RESUMEN

Epigenetic modifications are critical mechanisms that regulate many biological processes and establish normal cellular phenotypes. Aberrant epigenetic modifications are frequently linked to the development and maintenance of several diseases including cancer, inflammation and metabolic diseases and so on. The key proteins that mediate epigenetic modifications have been thus recognized as potential therapeutic targets for these diseases. Consequently, discovery of small molecule inhibitors for epigenetic targets has received considerable attention in recent years. Here, virtual screening methods and their applications in the discovery of epigenetic target inhibitors are the focus of this review. Newly emerging approaches or strategies including rescoring methods, docking pose filtering methods, machine learning methods and 3D molecular similarity methods were also underlined. They are expected to be employed for identifying novel inhibitors targeting epigenetic regulation more efficiently.


Asunto(s)
Descubrimiento de Drogas/métodos , Epigénesis Genética , Inteligencia Artificial , Sitios de Unión , Simulación por Computador , ADN-Citosina Metilasas/antagonistas & inhibidores , ADN-Citosina Metilasas/química , Evaluación Preclínica de Medicamentos/métodos , Inhibidores de Histona Desacetilasas/química , Histona Desacetilasas/química , Modelos Moleculares , Estructura Terciaria de Proteína , Bibliotecas de Moléculas Pequeñas , Programas Informáticos
16.
Nucleic Acids Res ; 42(Database issue): D1118-23, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24265219

RESUMEN

Here we describe an update of the Therapeutic Target Database (http://bidd.nus.edu.sg/group/ttd/ttd.asp) for better serving the bench-to-clinic communities and for enabling more convenient data access, processing and exchange. Extensive efforts from the research, industry, clinical, regulatory and management communities have been collectively directed at the discovery, investigation, application, monitoring and management of targeted therapeutics. Increasing efforts have been directed at the development of stratified and personalized medicines. These efforts may be facilitated by the knowledge of the efficacy targets and biomarkers of targeted therapeutics. Therefore, we added search tools for using the International Classification of Disease ICD-10-CM and ICD-9-CM codes to retrieve the target, biomarker and drug information (currently enabling the search of almost 900 targets, 1800 biomarkers and 6000 drugs related to 900 disease conditions). We added information of almost 1800 biomarkers for 300 disease conditions and 200 drug scaffolds for 700 drugs. We significantly expanded Therapeutic Target Database data contents to cover >2300 targets (388 successful and 461 clinical trial targets), 20 600 drugs (2003 approved and 3147 clinical trial drugs), 20,000 multitarget agents against almost 400 target-pairs and the activity data of 1400 agents against 300 cell lines.


Asunto(s)
Bases de Datos de Compuestos Químicos , Terapia Molecular Dirigida , Biomarcadores Farmacológicos , Enfermedad/clasificación , Humanos , Internet , Medicina de Precisión
17.
Bioorg Med Chem Lett ; 25(20): 4472-6, 2015 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-26346365

RESUMEN

A potential fluorescence probe for in vivo detection of cerebral ß-amyloid fibrils, (E)-2-(2-(2-(5-(dimethylamino)thiophen-2-yl)vinyl)-6-methyl-4H-pyran-4-ylidene)malononitrile (PT-1), was synthesized and evaluated. In experiments in vitro, PT-1 exhibited clear labeling of ß-amyloid fibrils and significant fluorescence changes upon binding to aggregated ß-amyloid fibrils. It also showed favorite kinetics in the brain, which is critical for cerebral imaging. In vivo fluorescence imaging with PT-1 and semi-quantitative analysis of the images further confirmed noninvasive visualization of cerebral ß-amyloid fibrils in vivo and obvious distinction between APP/PS1 transgenic mice and wild-type controls. The results demonstrate the potential of PT-1 as a novel fluorescence probe for noninvasive prediction of cerebral ß-amyloid fibrils.


Asunto(s)
Péptidos beta-Amiloides/análisis , Colorantes Fluorescentes/química , Nitrilos/química , Tiofenos/química , Animales , Fluorescencia , Colorantes Fluorescentes/administración & dosificación , Colorantes Fluorescentes/síntesis química , Inyecciones Intravenosas , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Moleculares , Estructura Molecular , Nitrilos/síntesis química , Tiofenos/síntesis química
18.
Bioorg Med Chem Lett ; 25(20): 4534-8, 2015 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-26342867

RESUMEN

In this investigation, a series of 6-phenylimidazo[2,1-b]thiazole derivatives were synthesized. Structure-activity relationship (SAR) analysis of these compounds based on cellular assays led to the discovery of a number of compounds that showed potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell line MV4-11, but very weak or no activity against FLT3-independent human cervical cancer cell line Hela. FLT3 kinase inhibition assays were then performed on the three most active compounds. Among these compounds, 6-(4-(3-(5-(tert-butyl)isoxazol- 3-yl)ureido)phenyl)-N-(3-(dimethylamino)propyl)imidazo[2,1-b]thiazole-3-carboxamide (19) exhibited the highest potency in both cellular (MV4-11, IC50: 0.002 µM) and enzymatic (FLT3, IC50: 0.022 µM) assays. Further in-depth in vitro anti-AML activity and mechanism of action studies were carried out on compound 19.


Asunto(s)
Descubrimiento de Drogas , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Tiazoles/farmacología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Estructura Molecular , Compuestos de Fenilurea/síntesis química , Compuestos de Fenilurea/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química , Tirosina Quinasa 3 Similar a fms/metabolismo
19.
Bioorg Med Chem Lett ; 25(22): 5449-53, 2015 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-26428871

RESUMEN

Despite a potential application of PRMT1 inhibitors in cancer treatment, very few of PRMT1 inhibitors have been reported. To obtain novel potent PRMT1 inhibitors, structure optimizations towards a hit compound, 4-((6-chloro-5-nitropyrimidin-4-yl)amino)benzimidamide, were carried out. A series of 4-((5-nitropyrimidin-4-yl)amino)benzimidamide derivatives were synthesized. Structure-activity relationship analysis led to the discovery of a number of PRMT1 inhibitors. The most potent compound corresponds to compound 6d, which showed an IC50 value of 2.0 µM against PRMT1. This compound also displayed a considerable anti-proliferative activity against three tumor cell lines, DLD-1, T24 and SH-SY-5Y, with IC50 values of 4.4 µM, 13.1 µM and 11.4 µM, respectively.


Asunto(s)
Bencimidazoles/química , Bencimidazoles/farmacología , Descubrimiento de Drogas , Modelos Biológicos , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Amidas/química , Amidas/farmacología , Animales , Sitios de Unión , Western Blotting , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Nitrocompuestos/química , Nitrocompuestos/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Relación Estructura-Actividad
20.
Molecules ; 20(5): 7620-36, 2015 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-25923513

RESUMEN

A series of quinoline derivatives was synthesized and biologically evaluated as Enhancer of Zeste Homologue 2 (EZH2) inhibitors. Structure-activity relationship (SAR) studies led to the discovery of 5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (5k), which displayed an IC50 value of 1.2 µM against EZH2, decreased global H3K27me3 level in cells and also showed good anti-viability activities against two tumor cell lines. Due to the low molecular weight and the fact that no quinoline derivative has been reported as an EZH2 inhibitor, this compound could serve as a lead compound for further optimization.


Asunto(s)
Aminoquinolinas/farmacología , Antineoplásicos/farmacología , Azepinas/farmacología , Complejo Represivo Polycomb 2/antagonistas & inhibidores , Aminoquinolinas/síntesis química , Antineoplásicos/síntesis química , Azepinas/síntesis química , Línea Celular Tumoral , Metilación de ADN/genética , Proteína Potenciadora del Homólogo Zeste 2 , Histonas/genética , Humanos , Neoplasias/patología , Relación Estructura-Actividad
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