Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 18 de 18
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Cell ; 167(1): 171-186.e15, 2016 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-27641501

RESUMO

While acute myeloid leukemia (AML) comprises many disparate genetic subtypes, one shared hallmark is the arrest of leukemic myeloblasts at an immature and self-renewing stage of development. Therapies that overcome differentiation arrest represent a powerful treatment strategy. We leveraged the observation that the majority of AML, despite their genetically heterogeneity, share in the expression of HoxA9, a gene normally downregulated during myeloid differentiation. Using a conditional HoxA9 model system, we performed a high-throughput phenotypic screen and defined compounds that overcame differentiation blockade. Target identification led to the unanticipated discovery that inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) enables myeloid differentiation in human and mouse AML models. In vivo, DHODH inhibitors reduced leukemic cell burden, decreased levels of leukemia-initiating cells, and improved survival. These data demonstrate the role of DHODH as a metabolic regulator of differentiation and point to its inhibition as a strategy for overcoming differentiation blockade in AML.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Terapia de Alvo Molecular , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Diferenciação Celular , Di-Hidro-Orotato Desidrogenase , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Ensaios de Triagem em Larga Escala , Proteínas de Homeodomínio/genética , Humanos , Leucemia Mieloide Aguda/genética , Camundongos , Células Mieloides/patologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Pirimidinas/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/isolamento & purificação , Bibliotecas de Moléculas Pequenas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Cell ; 161(6): 1252-65, 2015 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-26046436

RESUMO

Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the NIH launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science. This Perspective describes how novel small-molecule probes identified through the program are enabling the exploration of biological pathways and therapeutic hypotheses not otherwise testable. These experiences illustrate how small-molecule probes can help bridge the chasm between biological research and the development of medicines but also highlight the need to innovate the science of therapeutic discovery.


Assuntos
Descoberta de Drogas , Bibliotecas de Moléculas Pequenas , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , National Institutes of Health (U.S.) , Estados Unidos
3.
Nature ; 538(7625): 344-349, 2016 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-27602946

RESUMO

Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.


Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Azetidinas/uso terapêutico , Descoberta de Drogas , Estágios do Ciclo de Vida/efeitos dos fármacos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Animais , Antimaláricos/administração & dosagem , Antimaláricos/uso terapêutico , Compostos Azabicíclicos/administração & dosagem , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/farmacologia , Compostos Azabicíclicos/uso terapêutico , Azetidinas/administração & dosagem , Azetidinas/efeitos adversos , Azetidinas/farmacologia , Citosol/enzimologia , Modelos Animais de Doenças , Feminino , Fígado/efeitos dos fármacos , Fígado/parasitologia , Macaca mulatta/parasitologia , Malária Falciparum/prevenção & controle , Malária Falciparum/transmissão , Masculino , Camundongos , Fenilalanina-tRNA Ligase/antagonistas & inibidores , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Plasmodium falciparum/citologia , Plasmodium falciparum/enzimologia , Segurança
4.
J Am Chem Soc ; 141(26): 10225-10235, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31184885

RESUMO

It is challenging to incorporate stereochemical diversity and topographic complexity into DNA-encoded libraries (DELs) because DEL syntheses cannot fully exploit the capabilities of modern synthetic organic chemistry. Here, we describe the design, construction, and validation of DOS-DEL-1, a library of 107 616 DNA-barcoded chiral 2,3-disubsituted azetidines and pyrrolidines. We used stereospecific C-H arylation chemistry to furnish complex scaffolds primed for DEL synthesis, and we developed an improved on-DNA Suzuki reaction to maximize library quality. We then studied both the structural diversity of the library and the physicochemical properties of individual compounds using Tanimoto multifusion similarity analysis, among other techniques. These analyses revealed not only that most DOS-DEL-1 members have "drug-like" properties, but also that the library more closely resembles compound collections derived from diversity synthesis than those from other sources (e.g., commercial vendors). Finally, we performed validation screens against horseradish peroxidase and carbonic anhydrase IX, and we developed a novel, Poisson-based statistical framework to analyze the results. A set of assay positives were successfully translated into potent carbonic anhydrase inhibitors (IC50 = 20.1-68.7 nM), which confirmed the success of the synthesis and screening procedures. These results establish a strategy to synthesize DELs with scaffold-based stereochemical diversity and complexity that does not require the development of novel DNA-compatible chemistry.


Assuntos
Código de Barras de DNA Taxonômico , DNA/química , Inibidores Enzimáticos/química , Bibliotecas de Moléculas Pequenas/química , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Peroxidase do Rábano Silvestre/antagonistas & inibidores , Peroxidase do Rábano Silvestre/metabolismo , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Estereoisomerismo
5.
J Am Chem Soc ; 140(37): 11784-11790, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30133283

RESUMO

Target- and phenotype-agnostic assessments of biological activity have emerged as viable strategies for prioritizing scaffolds, structural features, and synthetic pathways in screening sets, with the goal of increasing performance diversity. Here, we describe the synthesis of a small library of functionalized stereoisomeric azetidines and its biological annotation by "cell painting," a multiplexed, high-content imaging assay capable of measuring many hundreds of compound-induced changes in cell morphology in a quantitative and unbiased fashion. Using this approach, we systematically compare the degrees to which a core scaffold's biological activity, inferred from its effects on cell morphology, is affected by variations in stereochemistry and appendages. We show that stereoisomerism and appendage diversification can produce effects of similar magnitude, and that the concurrent use of these strategies results in a broader sampling of biological activity.


Assuntos
Azetidinas/química , Bibliotecas de Moléculas Pequenas/química , Azetidinas/síntese química , Linhagem Celular Tumoral , Humanos , Conformação Molecular , Imagem Óptica , Bibliotecas de Moléculas Pequenas/síntese química , Estereoisomerismo
6.
Proc Natl Acad Sci U S A ; 111(30): 10911-6, 2014 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-25024206

RESUMO

High-throughput screening has become a mainstay of small-molecule probe and early drug discovery. The question of how to build and evolve efficient screening collections systematically for cell-based and biochemical screening is still unresolved. It is often assumed that chemical structure diversity leads to diverse biological performance of a library. Here, we confirm earlier results showing that this inference is not always valid and suggest instead using biological measurement diversity derived from multiplexed profiling in the construction of libraries with diverse assay performance patterns for cell-based screens. Rather than using results from tens or hundreds of completed assays, which is resource intensive and not easily extensible, we use high-dimensional image-based cell morphology and gene expression profiles. We piloted this approach using over 30,000 compounds. We show that small-molecule profiling can be used to select compound sets with high rates of activity and diverse biological performance.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos
7.
J Am Chem Soc ; 138(28): 8920-7, 2016 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-27398798

RESUMO

Organic chemists are able to synthesize molecules in greater number and chemical complexity than ever before. Yet, a majority of these compounds go untested in biological systems, and those that do are often tested long after the chemist can incorporate the results into synthetic planning. We propose the use of high-dimensional "multiplex" assays, which are capable of measuring thousands of cellular features in one experiment, to annotate rapidly and inexpensively the biological activities of newly synthesized compounds. This readily accessible and inexpensive "real-time" profiling method can be used in a prospective manner to facilitate, for example, the efficient construction of performance-diverse small-molecule libraries that are enriched in bioactives. Here, we demonstrate this concept by synthesizing ten triads of constitutionally isomeric compounds via complexity-generating photochemical and thermal rearrangements and measuring compound-induced changes in cellular morphology via an imaging-based "cell painting" assay. Our results indicate that real-time biological annotation can inform optimization efforts and library syntheses by illuminating trends relating to biological activity that would be difficult to predict if only chemical structure were considered. We anticipate that probe and drug discovery will benefit from the use of optimization efforts and libraries that implement this approach.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Bibliotecas de Moléculas Pequenas/química , Técnicas de Química Sintética , Isomerismo , Processos Fotoquímicos , Bibliotecas de Moléculas Pequenas/síntese química , Fatores de Tempo
8.
bioRxiv ; 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38746359

RESUMO

Ferroptosis is a cell death mechanism that has attracted significant attention as a potential basis for the development of new cancer therapies. Validation of ferroptosis biology in species commonly used in translation and pre-clinical development is a necessary foundation for enabling the advancement of such ferroptosis modulating drugs. Here, we demonstrate that canine cancer cells exhibit sensitivity to a wide range of ferroptosis-inducing perturbations in a manner indistinguishable from human cancer cells, and recapitulate characteristic patterns of ferroptotic response across tumor types seen in the human setting. The foundation provided herein establishes the dog as a relevant efficacy and toxicology model for ferroptosis and creates new opportunities to leverage the canine comparative oncology paradigm to accelerate the development of ferroptosis-inducing drugs for human cancer patients.

9.
Nat Commun ; 14(1): 1933, 2023 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-37024492

RESUMO

Identifying the spectrum of genes required for cancer cell survival can reveal essential cancer circuitry and therapeutic targets, but such a map remains incomplete for many cancer types. We apply genome-scale CRISPR-Cas9 loss-of-function screens to map the landscape of selectively essential genes in chordoma, a bone cancer with few validated targets. This approach confirms a known chordoma dependency, TBXT (T; brachyury), and identifies a range of additional dependencies, including PTPN11, ADAR, PRKRA, LUC7L2, SRRM2, SLC2A1, SLC7A5, FANCM, and THAP1. CDK6, SOX9, and EGFR, genes previously implicated in chordoma biology, are also recovered. We find genomic and transcriptomic features that predict specific dependencies, including interferon-stimulated gene expression, which correlates with ADAR dependence and is elevated in chordoma. Validating the therapeutic relevance of dependencies, small-molecule inhibitors of SHP2, encoded by PTPN11, have potent preclinical efficacy against chordoma. Our results generate an emerging map of chordoma dependencies to enable biological and therapeutic hypotheses.


Assuntos
Neoplasias Ósseas , Cordoma , Humanos , Cordoma/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Genes Essenciais , Perfilação da Expressão Gênica , Transcriptoma , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Proteínas Reguladoras de Apoptose/genética , DNA Helicases/metabolismo
10.
Nat Commun ; 14(1): 1364, 2023 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-36914634

RESUMO

Robust, generalizable approaches to identify compounds efficiently with undesirable mechanisms of action in complex cellular assays remain elusive. Such a process would be useful for hit triage during high-throughput screening and, ultimately, predictive toxicology during drug development. Here we generate cell painting and cellular health profiles for 218 prototypical cytotoxic and nuisance compounds in U-2 OS cells in a concentration-response format. A diversity of compounds that cause cellular damage produces bioactive cell painting morphologies, including cytoskeletal poisons, genotoxins, nonspecific electrophiles, and redox-active compounds. Further, we show that lower quality lysine acetyltransferase inhibitors and nonspecific electrophiles can be distinguished from more selective counterparts. We propose that the purposeful inclusion of cytotoxic and nuisance reference compounds such as those profiled in this resource will help with assay optimization and compound prioritization in complex cellular assays like cell painting.


Assuntos
Ensaios de Triagem em Larga Escala , Oxirredução
11.
Clin Transl Sci ; 14(5): 1719-1724, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33742785

RESUMO

"Knowledge graphs" (KGs) have become a common approach for representing biomedical knowledge. In a KG, multiple biomedical data sets can be linked together as a graph representation, with nodes representing entities, such as "chemical substance" or "genes," and edges representing predicates, such as "causes" or "treats." Reasoning and inference algorithms can then be applied to the KG and used to generate new knowledge. We developed three KG-based question-answering systems as part of the Biomedical Data Translator program. These systems are typically tested and evaluated using traditional software engineering tools and approaches. In this study, we explored a team-based approach to test and evaluate the prototype "Translator Reasoners" through the application of Medical College Admission Test (MCAT) questions. Specifically, we describe three "hackathons," in which the developers of each of the three systems worked together with a moderator to determine whether the applications could be used to solve MCAT questions. The results demonstrate progressive improvement in system performance, with 0% (0/5) correct answers during the first hackathon, 75% (3/4) correct during the second hackathon, and 100% (5/5) correct during the final hackathon. We discuss the technical and sociologic lessons learned and conclude that MCAT questions can be applied successfully in the context of moderated hackathons to test and evaluate prototype KG-based question-answering systems, identify gaps in current capabilities, and improve performance. Finally, we highlight several published clinical and translational science applications of the Translator Reasoners.


Assuntos
Reconhecimento Automatizado de Padrão/métodos , Ciência Translacional Biomédica/métodos , Algoritmos , Teste de Admissão Acadêmica/estatística & dados numéricos , Conjuntos de Dados como Assunto , Humanos
12.
Cell Rep Med ; 2(1): 100188, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33521702

RESUMO

Chordomas are rare spinal tumors addicted to expression of the developmental transcription factor brachyury. In chordomas, brachyury is super-enhancer associated and preferentially downregulated by pharmacologic transcriptional CDK inhibition, leading to cell death. To understand the underlying basis of this sensitivity, we dissect the brachyury transcription regulatory network and compare the consequences of brachyury degradation with transcriptional CDK inhibition. Brachyury defines the chordoma super-enhancer landscape and autoregulates through binding its super-enhancer, and its locus forms a transcriptional condensate. Transcriptional CDK inhibition and brachyury degradation disrupt brachyury autoregulation, leading to loss of its transcriptional condensate and transcriptional program. Compared with transcriptional CDK inhibition, which globally downregulates transcription, leading to cell death, brachyury degradation is much more selective, inducing senescence and sensitizing cells to anti-apoptotic inhibition. These data suggest that brachyury downregulation is a core tenet of transcriptional CDK inhibition and motivates developing strategies to target brachyury and its autoregulatory feedback loop.


Assuntos
Biomarcadores Tumorais/genética , Cordoma/genética , Quinases Ciclina-Dependentes/genética , Proteínas Fetais/genética , Proteínas de Neoplasias/genética , Neoplasias da Coluna Vertebral/genética , Proteínas com Domínio T/genética , Sequência de Bases , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Cordoma/metabolismo , Cordoma/patologia , Quinases Ciclina-Dependentes/metabolismo , Proteínas Fetais/metabolismo , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Células HEK293 , Histonas/genética , Histonas/metabolismo , Humanos , Queratina-18/genética , Queratina-18/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas de Neoplasias/metabolismo , Proteólise , Transdução de Sinais , Neoplasias da Coluna Vertebral/metabolismo , Neoplasias da Coluna Vertebral/patologia , Proteínas com Domínio T/metabolismo
13.
Nat Med ; 25(2): 292-300, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30664779

RESUMO

Chordoma is a primary bone cancer with no approved therapy1. The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors2,3. Here we describe the discovery of therapeutically targetable chordoma dependencies via genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling. These systematic approaches reveal that the developmental transcription factor T (brachyury; TBXT) is the top selectively essential gene in chordoma, and that transcriptional cyclin-dependent kinase (CDK) inhibitors targeting CDK7/12/13 and CDK9 potently suppress chordoma cell proliferation. In other cancer types, transcriptional CDK inhibitors have been observed to downregulate highly expressed, enhancer-associated oncogenic transcription factors4,5. In chordoma, we find that T is associated with a 1.5-Mb region containing 'super-enhancers' and is the most highly expressed super-enhancer-associated transcription factor. Notably, transcriptional CDK inhibition leads to preferential and concentration-dependent downregulation of cellular brachyury protein levels in all models tested. In vivo, CDK7/12/13-inhibitor treatment substantially reduces tumor growth. Together, these data demonstrate small-molecule targeting of brachyury transcription factor addiction in chordoma, identify a mechanism of T gene regulation that underlies this therapeutic strategy, and provide a blueprint for applying systematic genetic and chemical screening approaches to discover vulnerabilities in genomically quiet cancers.


Assuntos
Cordoma/metabolismo , Proteínas Fetais/metabolismo , Proteínas com Domínio T/metabolismo , Fatores de Transcrição/metabolismo , Proliferação de Células/efeitos dos fármacos , Cordoma/genética , Cordoma/patologia , Quinases Ciclina-Dependentes/metabolismo , Regulação para Baixo/efeitos dos fármacos , Genes Essenciais , Humanos , Inibidores de Proteínas Quinases/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia
14.
Nat Genet ; 50(7): 937-943, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29955178

RESUMO

Functional redundancy shared by paralog genes may afford protection against genetic perturbations, but it can also result in genetic vulnerabilities due to mutual interdependency1-5. Here, we surveyed genome-scale short hairpin RNA and CRISPR screening data on hundreds of cancer cell lines and identified MAGOH and MAGOHB, core members of the splicing-dependent exon junction complex, as top-ranked paralog dependencies6-8. MAGOHB is the top gene dependency in cells with hemizygous MAGOH deletion, a pervasive genetic event that frequently occurs due to chromosome 1p loss. Inhibition of MAGOHB in a MAGOH-deleted context compromises viability by globally perturbing alternative splicing and RNA surveillance. Dependency on IPO13, an importin-ß receptor that mediates nuclear import of the MAGOH/B-Y14 heterodimer9, is highly correlated with dependency on both MAGOH and MAGOHB. Both MAGOHB and IPO13 represent dependencies in murine xenografts with hemizygous MAGOH deletion. Our results identify MAGOH and MAGOHB as reciprocal paralog dependencies across cancer types and suggest a rationale for targeting the MAGOHB-IPO13 axis in cancers with chromosome 1p deletion.


Assuntos
Cromossomos Humanos Par 1 , Neoplasias/genética , Animais , Linhagem Celular Tumoral , Núcleo Celular/genética , Éxons/genética , Feminino , Deleção de Genes , Células HEK293 , Humanos , Carioferinas/genética , Camundongos , Camundongos Nus , Proteínas Nucleares/genética , Splicing de RNA/genética , RNA Interferente Pequeno/genética
15.
Gigascience ; 6(12): 1-5, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28327978

RESUMO

Background: Large-scale image sets acquired by automated microscopy of perturbed samples enable a detailed comparison of cell states induced by each perturbation, such as a small molecule from a diverse library. Highly multiplexed measurements of cellular morphology can be extracted from each image and subsequently mined for a number of applications. Findings: This microscopy dataset includes 919 265 five-channel fields of view, representing 30 616 tested compounds, available at "The Cell Image Library" (CIL) repository. It also includes data files containing morphological features derived from each cell in each image, both at the single-cell level and population-averaged (i.e., per-well) level; the image analysis workflows that generated the morphological features are also provided. Quality-control metrics are provided as metadata, indicating fields of view that are out-of-focus or containing highly fluorescent material or debris. Lastly, chemical annotations are supplied for the compound treatments applied. Conclusions: Because computational algorithms and methods for handling single-cell morphological measurements are not yet routine, the dataset serves as a useful resource for the wider scientific community applying morphological (image-based) profiling. The dataset can be mined for many purposes, including small-molecule library enrichment and chemical mechanism-of-action studies, such as target identification. Integration with genetically perturbed datasets could enable identification of small-molecule mimetics of particular disease- or gene-related phenotypes that could be useful as probes or potential starting points for development of future therapeutics.


Assuntos
Processamento de Imagem Assistida por Computador , Bibliotecas de Moléculas Pequenas , Linhagem Celular , Células/efeitos dos fármacos , Células/ultraestrutura , Humanos
16.
Org Lett ; 18(24): 6280-6283, 2016 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-27978655

RESUMO

Sp3-rich compounds are underrepresented in libraries for probe- and drug-discovery, despite their promise of extending the range of accessible molecular shapes beyond planar geometries. With this in mind, a collection of single-enantiomer bicyclic, fused cyclopentenones underpinned by a complexity-generating Pauson-Khand cyclization was synthesized. A fingerprint of biological actions of these compounds was determined immediately after synthesis using real-time annotation-a process relying on multiplexed measurements of alterations in cell morphological features.


Assuntos
Ciclopentanos/síntese química , Ciclopentanos/farmacologia , Imagem Óptica , Pironas/síntese química , Pironas/farmacologia , Contagem de Células , Linhagem Celular Tumoral , Ciclização , Ciclopentanos/química , Humanos , Conformação Molecular , Estereoisomerismo
17.
Cancer Discov ; 5(11): 1210-23, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26482930

RESUMO

UNLABELLED: Identifying genetic alterations that prime a cancer cell to respond to a particular therapeutic agent can facilitate the development of precision cancer medicines. Cancer cell-line (CCL) profiling of small-molecule sensitivity has emerged as an unbiased method to assess the relationships between genetic or cellular features of CCLs and small-molecule response. Here, we developed annotated cluster multidimensional enrichment analysis to explore the associations between groups of small molecules and groups of CCLs in a new, quantitative sensitivity dataset. This analysis reveals insights into small-molecule mechanisms of action, and genomic features that associate with CCL response to small-molecule treatment. We are able to recapitulate known relationships between FDA-approved therapies and cancer dependencies and to uncover new relationships, including for KRAS-mutant cancers and neuroblastoma. To enable the cancer community to explore these data, and to generate novel hypotheses, we created an updated version of the Cancer Therapeutic Response Portal (CTRP v2). SIGNIFICANCE: We present the largest CCL sensitivity dataset yet available, and an analysis method integrating information from multiple CCLs and multiple small molecules to identify CCL response predictors robustly. We updated the CTRP to enable the cancer research community to leverage these data and analyses.


Assuntos
Biologia Computacional/métodos , Resistencia a Medicamentos Antineoplásicos/genética , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias/genética , Bibliotecas de Moléculas Pequenas , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Análise por Conglomerados , Conjuntos de Dados como Assunto , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Humanos , Mutação , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia
18.
J Biomol Screen ; 19(5): 738-48, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24710340

RESUMO

Understanding the structure-activity relationships (SARs) of small molecules is important for developing probes and novel therapeutic agents in chemical biology and drug discovery. Increasingly, multiplexed small-molecule profiling assays allow simultaneous measurement of many biological response parameters for the same compound (e.g., expression levels for many genes or binding constants against many proteins). Although such methods promise to capture SARs with high granularity, few computational methods are available to support SAR analyses of high-dimensional compound activity profiles. Many of these methods are not generally applicable or reduce the activity space to scalar summary statistics before establishing SARs. In this article, we present a versatile computational method that automatically extracts interpretable SAR rules from high-dimensional profiling data. The rules connect chemical structural features of compounds to patterns in their biological activity profiles. We applied our method to data from novel cell-based gene-expression and imaging assays collected on more than 30,000 small molecules. Based on the rules identified for this data set, we prioritized groups of compounds for further study, including a novel set of putative histone deacetylase inhibitors.


Assuntos
Biologia Computacional/métodos , Relação Estrutura-Atividade , Automação , Química Farmacêutica/métodos , Análise por Conglomerados , Mineração de Dados/métodos , Descoberta de Drogas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Inibidores de Histona Desacetilases/química , Humanos , Software
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA