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1.
Sci Rep ; 10(1): 20970, 2020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-33262371

RESUMEN

Genetic evidence of disease association has often been used as a basis for selecting of drug targets for complex common diseases. Likewise, the propagation of genetic evidence through gene or protein interaction networks has been shown to accurately infer novel disease associations at genes for which no direct genetic evidence can be observed. However, an empirical test of the utility of combining these approaches for drug discovery has been lacking. In this study, we examine genetic associations arising from an analysis of 648 UK Biobank GWAS and evaluate whether targets identified as proxies of direct genetic hits are enriched for successful drug targets, as measured by historical clinical trial data. We find that protein networks formed from specific functional linkages such as protein complexes and ligand-receptor pairs are suitable for even naïve guilt-by-association network propagation approaches. In addition, more sophisticated approaches applied to global protein-protein interaction networks and pathway databases, also successfully retrieve targets enriched for clinically successful drug targets. We conclude that network propagation of genetic evidence can be used for drug target identification.


Asunto(s)
Redes Reguladoras de Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Terapia Molecular Dirigida , Sistemas de Liberación de Medicamentos , Humanos , Hiperlipidemias/genética , Modelos Genéticos , Transducción de Señal/genética
2.
Nat Genet ; 52(10): 1122-1131, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32895551

RESUMEN

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.


Asunto(s)
Proteínas Sanguíneas/genética , Predisposición Genética a la Enfermedad , Análisis de la Aleatorización Mendeliana , Proteoma/genética , Estudio de Asociación del Genoma Completo , Humanos , Fenotipo , Polimorfismo de Nucleótido Simple/genética
3.
Drug Discov Today ; 24(6): 1232-1236, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30935985

RESUMEN

Genome-wide association studies (GWAS) have made considerable progress and there is emerging evidence that genetics-based targets can lead to 28% more launched drugs. We analyzed 1589 GWAS across 1456 pathways to translate these often imprecise genetic loci into therapeutic hypotheses for 182 diseases. These pathway-based genetic targets were validated by testing whether current drug targets were enriched in the pathway space for the same indication. Remarkably, 30% of diseases had significantly more targets in these pathways than expected by chance; the comparable number for GWAS alone (without pathway analysis) was zero. This study shows that a systematic global pathway analysis can translate genetic findings into therapeutic hypotheses for both new drug discovery and repositioning opportunities for current drugs.


Asunto(s)
Descubrimiento de Drogas/métodos , Reposicionamiento de Medicamentos/métodos , Sitios Genéticos/genética , Preparaciones Farmacéuticas/química , Estudio de Asociación del Genoma Completo/métodos , Humanos
4.
PLoS One ; 14(4): e0215033, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31002701

RESUMEN

Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by cytochrome P450 epoxygenation of arachidonic acid, which are metabolized by EPHX2 (epoxide hydrolase 2, alias soluble epoxide hydrolase or sEH). EETs have pleiotropic effects, including anti-inflammatory activity. Using a Connectivity Map (CMAP) approach, we identified an inverse-correlation between an exemplar EPHX2 inhibitor (EPHX2i) compound response and an inflammatory bowel disease patient-derived signature. To validate the gene-disease link, we tested a pre-clinical tool EPHX2i (GSK1910364) in a mouse disease model, where it showed improved outcomes comparable to or better than the positive control Cyclosporin A. Up-regulation of cytoprotective genes and down-regulation of proinflammatory cytokine production were observed in colon samples obtained from EPHX2i-treated mice. Follow-up immunohistochemistry analysis verified the presence of EPHX2 protein in infiltrated immune cells from Crohn's patient tissue biopsies. We further demonstrated that GSK2256294, a clinical EPHX2i, reduced the production of IL2, IL12p70, IL10 and TNFα in both ulcerative colitis and Crohn's disease patient-derived explant cultures. Interestingly, GSK2256294 reduced IL4 and IFNγ in ulcerative colitis, and IL1ß in Crohn's disease specifically, suggesting potential differential effects of GSK2256294 in these two diseases. Taken together, these findings suggest a novel therapeutic use of EPHX2 inhibition for IBD.


Asunto(s)
Colitis/tratamiento farmacológico , Ciclohexilaminas/farmacología , Evaluación Preclínica de Medicamentos/métodos , Epóxido Hidrolasas/antagonistas & inhibidores , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Triazinas/farmacología , Animales , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Citocinas/metabolismo , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Ratones , Ratones Endogámicos C57BL
5.
BMC Bioinformatics ; 20(1): 69, 2019 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-30736745

RESUMEN

BACKGROUND: Determining which target to pursue is a challenging and error-prone first step in developing a therapeutic treatment for a disease, where missteps are potentially very costly given the long-time frames and high expenses of drug development. With current informatics technology and machine learning algorithms, it is now possible to computationally discover therapeutic hypotheses by predicting clinically promising drug targets based on the evidence associating drug targets with disease indications. We have collected this evidence from Open Targets and additional databases that covers 17 sources of evidence for target-indication association and represented the data as a tensor of 21,437 × 2211 × 17. RESULTS: As a proof-of-concept, we identified examples of successes and failures of target-indication pairs in clinical trials across 875 targets and 574 disease indications to build a gold-standard data set of 6140 known clinical outcomes. We designed and executed three benchmarking strategies to examine the performance of multiple machine learning models: Logistic Regression, LASSO, Random Forest, Tensor Factorization and Gradient Boosting Machine. With 10-fold cross-validation, tensor factorization achieved AUROC = 0.82 ± 0.02 and AUPRC = 0.71 ± 0.03. Across multiple validation schemes, this was comparable or better than other methods. CONCLUSION: In this work, we benchmarked a machine learning technique called tensor factorization for the problem of predicting clinical outcomes of therapeutic hypotheses. Results have shown that this method can achieve equal or better prediction performance compared with a variety of baseline models. We demonstrate one application of the method to predict outcomes of trials on novel indications of approved drug targets. This work can be expanded to targets and indications that have never been clinically tested and proposing novel target-indication hypotheses. Our proposed biologically-motivated cross-validation schemes provide insight into the robustness of the prediction performance. This has significant implications for all future methods that try to address this seminal problem in drug discovery.


Asunto(s)
Algoritmos , Descubrimiento de Drogas , Modelos Teóricos , Teorema de Bayes , Benchmarking , Ensayos Clínicos como Asunto , Sistemas de Liberación de Medicamentos/métodos , Humanos , Modelos Logísticos
6.
PLoS Comput Biol ; 14(5): e1006142, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29782487

RESUMEN

Target selection is the first and pivotal step in drug discovery. An incorrect choice may not manifest itself for many years after hundreds of millions of research dollars have been spent. We collected a set of 332 targets that succeeded or failed in phase III clinical trials, and explored whether Omic features describing the target genes could predict clinical success. We obtained features from the recently published comprehensive resource: Harmonizome. Nineteen features appeared to be significantly correlated with phase III clinical trial outcomes, but only 4 passed validation schemes that used bootstrapping or modified permutation tests to assess feature robustness and generalizability while accounting for target class selection bias. We also used classifiers to perform multivariate feature selection and found that classifiers with a single feature performed as well in cross-validation as classifiers with more features (AUROC = 0.57 and AUPR = 0.81). The two predominantly selected features were mean mRNA expression across tissues and standard deviation of expression across tissues, where successful targets tended to have lower mean expression and higher expression variance than failed targets. This finding supports the conventional wisdom that it is favorable for a target to be present in the tissue(s) affected by a disease and absent from other tissues. Overall, our results suggest that it is feasible to construct a model integrating interpretable target features to inform target selection. We anticipate deeper insights and better models in the future, as researchers can reuse the data we have provided to improve methods for handling sample biases and learn more informative features. Code, documentation, and data for this study have been deposited on GitHub at https://github.com/arouillard/omic-features-successful-targets.


Asunto(s)
Descubrimiento de Drogas/métodos , Perfilación de la Expresión Génica/métodos , Transcriptoma/efectos de los fármacos , Animales , Línea Celular , Biología Computacional , Humanos , Ratones , Transducción de Señal/efectos de los fármacos
7.
Sci Rep ; 6: 36205, 2016 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-27824084

RESUMEN

It is commonly assumed that drug targets are expressed in tissues relevant to their indicated diseases, even under normal conditions. While multiple anecdotal cases support this hypothesis, a comprehensive study has not been performed to verify it. We conducted a systematic analysis to assess gene and protein expression for all targets of marketed and phase III drugs across a diverse collection of normal human tissues. For 87% of gene-disease pairs, the target is expressed in a disease-affected tissue under healthy conditions. This result validates the importance of confirming expression of a novel drug target in an appropriate tissue for each disease indication and strengthens previous findings showing that targets of efficacious drugs should be expressed in relevant tissues under normal conditions. Further characterization of the remaining 13% of gene-disease pairs revealed that most genes are expressed in a different tissue linked to another disease. Our analysis demonstrates the value of extensive tissue specific expression resources.both in terms of tissue and cell diversity as well as techniques used to measure gene expression.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Predisposición Genética a la Enfermedad/genética , Proteómica/métodos , Ensayos Clínicos Fase III como Asunto , Redes Reguladoras de Genes , Humanos , Terapia Molecular Dirigida , Análisis de Secuencia por Matrices de Oligonucleótidos , Especificidad de Órganos
9.
Nat Rev Drug Discov ; 15(9): 596-597, 2016 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-28184040

RESUMEN

This corrects the article DOI: 10.1038/nrd.2016.164.

10.
J Biomol Screen ; 19(5): 782-90, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24563424

RESUMEN

Small-molecule screens are an integral part of drug discovery. Public domain data in PubChem alone represent more than 158 million measurements, 1.2 million molecules, and 4300 assays. We conducted a global analysis of these data, building a network of assays and connecting the assays if they shared nonpromiscuous active molecules. This network spans both phenotypic and target-based screens, recapitulates known biology, and identifies new polypharmacology. Phenotypic screens are extremely important for drug discovery, contributing to the discovery of a large proportion of new drugs. Connections between phenotypic and biochemical, target-based screens can suggest strategies for repurposing both small-molecule and biologic drugs. For example, a screen for molecules that prevent cell death from a mutated version of superoxide-dismutase is linked with ALOX15. This connection suggests a therapeutic role for ALOX15 inhibitors in amyotrophic lateral sclerosis. An interactive version of the network is available online (http://swami.wustl.edu/flow/assay_network.html).


Asunto(s)
Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Bioensayo/métodos , Descubrimiento de Drogas , Ensayos Analíticos de Alto Rendimiento/métodos , Algoritmos , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Araquidonato 15-Lipooxigenasa/química , Araquidonato 15-Lipooxigenasa/genética , Área Bajo la Curva , Humanos , Inhibidores de la Lipooxigenasa/química , Modelos Estadísticos , Mutación , Fenotipo , Curva ROC
11.
Arterioscler Thromb Vasc Biol ; 30(11): 2256-63, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20689074

RESUMEN

OBJECTIVE: To evaluate whether a p38α/ß mitogen-activated protein kinase inhibitor, SB-681323, would limit the elevation of an inflammatory marker, high-sensitivity C-reactive protein (hsCRP), after a percutaneous coronary intervention (PCI). METHODS AND RESULTS: Coronary artery stents provide benefit by maintaining lumen patency but may incur vascular trauma and inflammation, leading to myocardial damage. A key mediator for such stress signaling is p38 mitogen-activated protein kinase. Patients with angiographically documented coronary artery disease receiving stable statin therapy and about to undergo PCI were randomly selected to receive SB-681323, 7.5 mg (n=46), or placebo (n=46) daily for 28 days, starting 3 days before PCI. On day 3, before PCI, hsCRP was decreased in the SB-681323 group relative to the placebo group (29% lower; P=0.02). After PCI, there was a statistically significant attenuation in the increase in hsCRP in the SB-681323 group relative to the placebo group (37% lower on day 5 [P=0.04]; and 40% lower on day 28 [P=0.003]). There were no adverse safety signals after 28 days of treatment with SB-681323. CONCLUSIONS: In the setting of statin therapy, SB-681323 significantly attenuated the post-PCI inflammatory response, as measured by hsCRP. This inflammatory dampening implicates p38 mitogen-activated protein kinase in the poststent response, potentially defining an avenue to limit poststent restenosis.


Asunto(s)
Angioplastia Coronaria con Balón/efectos adversos , Antiinflamatorios/uso terapéutico , Vasos Coronarios/lesiones , Stents/efectos adversos , Lesiones del Sistema Vascular/prevención & control , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Anciano , Proteína C-Reactiva/análisis , Enfermedad de la Arteria Coronaria/terapia , Método Doble Ciego , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inflamación/sangre , Masculino , Persona de Mediana Edad , Implantación de Prótesis/efectos adversos , Lesiones del Sistema Vascular/sangre , Lesiones del Sistema Vascular/etiología
12.
Arterioscler Thromb Vasc Biol ; 27(5): 1115-22, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17322100

RESUMEN

OBJECTIVE: Reduced plasma concentrations of high-density lipoprotein-cholesterol (HDL-C) are a significant risk factor for cardiovascular disease. Mechanisms that regulate HDL-C concentrations represent an important area of investigation. METHODS AND RESULTS: Comparative transcriptome analyses of monocyte-derived macrophages (MDM) from a large population of low HDL-C subjects and age- and sex-matched controls revealed a cluster of inflammatory genes highly expressed in low HDL-C subjects. The expression levels of peroxisome proliferator activated receptor (PPAR) gamma and several antioxidant metallothionein genes were decreased in MDM from all low HDL-C groups compared with controls, as was the expression of other genes regulated by PPARgamma, including CD36, adipocyte fatty acid binding protein (FABP4), and adipophilin (ADFP). In contrast, PPARdelta expression was increased in MDM from low HDL-C groups. Quantitative RT-PCR corroborated all major findings from the microarray analysis in two separate patient cohorts. Expression of several inflammatory cytokine genes including interleukin 1beta, interleukin 8, and tumor necrosis factor alpha were highly increased in low HDL-C subjects. CONCLUSIONS: The activated proinflammatory state of monocytes and MDM in low HDL-C subjects constitutes a novel parameter of risk associated with HDL deficiency, related to altered expression of metallothionein genes and the reciprocal regulation of PPARgamma and PPARdelta.


Asunto(s)
HDL-Colesterol/deficiencia , Expresión Génica , Hipolipoproteinemias/sangre , Macrófagos/metabolismo , PPAR delta/genética , PPAR gamma/genética , ARN/genética , Aterosclerosis/sangre , Aterosclerosis/etiología , Biomarcadores/sangre , HDL-Colesterol/sangre , Proteínas de Unión a Ácidos Grasos/biosíntesis , Proteínas de Unión a Ácidos Grasos/genética , Genotipo , Humanos , Hipolipoproteinemias/complicaciones , Hipolipoproteinemias/genética , Interleucina-1beta/biosíntesis , Interleucina-1beta/genética , Interleucina-8/biosíntesis , Interleucina-8/genética , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Análisis por Micromatrices , Mutación , PPAR delta/biosíntesis , PPAR gamma/biosíntesis , Perilipina-2 , Fenotipo , Reacción en Cadena de la Polimerasa , Factores de Riesgo , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genética
13.
Cancer Res ; 62(6): 1797-801, 2002 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-11912157

RESUMEN

Resistance to chemotherapy targeting microtubules could be partially because of the delay in chromosome condensation and segregation during mitosis. The Chfr pathway has been defined recently, and its activation causes a delay in chromosome condensation in response to mitotic stress. Because Chfr contains a RING-finger domain, we tested whether Chfr inhibits chromosome condensation through an ubiquitin (ubiquitin)-dependent pathway. In the presence of purified E1, Ubc4, or Ubc5, and ubiquitin, Chfr catalyzes its own ubiquitination in vitro, an activity requiring the RING domain. In vivo, overexpressed Chfr but not a RING domain mutant is spontaneously ubiquitinated. Our studies with DLD1 cells stably expressing wild-type Chfr and Chfr lacking the RING domain indicated that the RING-finger deletion mutant was defective in inhibiting chromosome condensation after Taxol treatment. In addition, Chfr expression increases the survival rate after Taxol treatment, an activity requiring the RING domain. Preliminary studies indicate that Chfr expression is cell cycle regulated and is dependent on its ubiquitin ligase activity. It is very likely that the Chfr-mediated ubiquitin-dependent pathway is a critical component of the response to mitotic stress.


Asunto(s)
Proteínas de Ciclo Celular/fisiología , Ligasas/metabolismo , Mitosis/fisiología , Proteínas de Neoplasias , Ubiquitina/metabolismo , Secuencia de Aminoácidos , Antineoplásicos/farmacología , Ciclo Celular/fisiología , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Daño del ADN , Humanos , Mitosis/efectos de los fármacos , Datos de Secuencia Molecular , Paclitaxel/farmacología , Proteínas de Unión a Poli-ADP-Ribosa , Estructura Terciaria de Proteína , Estrés Fisiológico , Topotecan/farmacología , Células Tumorales Cultivadas , Ubiquitina-Proteína Ligasas
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