Validating cancer drug targets

Benson, Jalen; Chen, Ying Nan P; Cornell-Kennon, Susan; Dorsch, Marion; Kim, Sunkyu; Leszczyniecka, Magdalena; Sellers, William R.; Lengauer, Christoph

doi:10.1038/nature04873

Cited by 146 publications

(86 citation statements)

References 49 publications

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“…Potential options for genotype-specific anticancer therapies arising from FA pathway inactivation in tumors will require suitable preclinical models, for which stringent and universal validation criteria have not yet been established (47). Various models of FA gene defects have been developed, each of which has certain limitations when used for pharmacogenomic studies.…”

Section: Clinical Translational Advancesmentioning

confidence: 99%

Targeting Fanconi Anemia/BRCA2 Pathway Defects in Cancer: The Significance of Preclinical Pharmacogenomic Models

Gallmeier

Kern

2007

Clinical Cancer Research

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Defects in the Fanconi anemia (FA) pathway occur in subsets of diverse human cancers. The hypersensitivity of FA pathway-deficient cells to DNA interstrand cross-linking and possibly other agents renders these genes attractive targets for a genotype-based, individualized anticancer therapy. A prerequisite before clinical trials is the validation and quantification of this hypersensitivity in suitable preclinical pharmacogenomic models. In addition, the effects of combinational therapy need to be evaluated and novel agents sought.We discuss here the pitfalls and limitations in the interpretation of common FA models when applied to the validation of FA gene defects as therapeutic targets. In general, all preclinical models are prone to certain artifacts and, thus, promising results in a single or few models rarely translate into clinical success. Nevertheless, the extraordinary robustness of FA pathway-deficient cells to interstrand cross-linking agents, which are observable in virtually any model independent of species, cell type, or technique used to engineer the gene defect, in various in vitro and in vivo settings, renders these gene defects particularly attractive for targeted therapy. Clinical trials are now under way.

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Section: Clinical Translational Advancesmentioning

confidence: 99%

Targeting Fanconi Anemia/BRCA2 Pathway Defects in Cancer: The Significance of Preclinical Pharmacogenomic Models

Gallmeier

Kern

2007

Clinical Cancer Research

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“…A análise do nível de expressão de proteínas de um mesmo organismo (e.g., normais, superexpressas, deficientes) pode relevar características estruturais e funcionais que permitam diferenciar tecidos patológicos dos sadios, levando à seleção de alvos para o planejamento de fármacos. 19 No caso de doenças humanas causadas por micro-organismos, uma investigação das principais vias bioquímicas possibilita a identificação de proteínas essenciais para o crescimento e desenvolvimento do micro-organismo alvo (e.g., bactéria, parasita, fungo). Uma análise comparativa dos organismos pode levar, preferencialmente, à seleção de proteínas ausentes no hospedeiro (i.e., específicas para o patógeno) ou então com importantes diferenças estruturais em relação às proteínas que desempenham função análoga em humanos.…”

Section: Seleção Do Alvo Molecularunclassified

Integração das técnicas de triagem virtual e triagem biológica automatizada em alta escala: oportunidades e desafios em P&D de fármacos

Ferreira¹,

Oliva²,

Andricopulo³

2011

Quím. Nova

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Recebido em 16/1/11; aceito em 2/6/11; publicado na web em 26/7/11 INTEGRATING VIRTUAL AND HIGH-THROUGHPUT SCREENING: OPPORTUNITIES AND CHALLENGES IN DRUG RESEARCH AND DEVELOPMENT. High-throughput screening (HTS) and virtual screening (VS) are useful methods employed in drug discovery, allowing the identification of promising hits for lead optimization. The efficiency of these approaches depends on a number of factors, such as the organization of high quality databases of compounds and the parameterization of essential components of the screen process. This brief review presents the basic principles of the HTS and VS methods, as well as a perspective of the utility and integration of these drug design approaches, highlighting current opportunities and future challenges in medicinal chemistry.Keywords: high-throughput screening; virtual screening; drug design. INTRODUÇÃOA descoberta de novos fármacos é um grande desafio para a indústria farmacêutica moderna. Os altos investimentos na área de pesquisa e desenvolvimento (P&D) contrastam com o número de novos medicamentos que têm chegado ao mercado nos últimos anos. 1 Este complexo panorama tem forçado a adoção de novas estratégias com o objetivo de aumentar a eficiência do processo de P&D, tendo como alicerces as inovações científicas, tecnológicas e empresariais.Considerando-se o expressivo número de alvos biológicos (proteínas alvo) promissores para o planejamento de fármacos, as técnicas de triagem biológica automatizada em alta escala (HTS -high throughput screening) e de triagem virtual (VS -virtual screening) têm ocupado papel de destaque entre as estratégias modernas exploradas na identificação de novas substâncias bioativas. Desde o seu surgimento, a HTS tem sido amplamente utilizada pela indústria farmacêutica, propiciando a avaliação de milhões de compostos contra proteínas alvo. Embora esta estratégia tenha despertado a esperança de uma revolução na descoberta de substâncias bioativas, em pouco tempo as suas limitações ficaram evidentes. 2 A ocorrência de um número elevado de falso-positivos, identificados inicialmente como hits (termo em inglês para designar um novo ligante ou composto bioativo) nos ensaios bioquímicos em alta escala pode ser destacada como um dos grandes problemas. 3 Os múltiplos modos de interação ou mecanismos de ação apresentados pelos diferentes hits selecionados podem também ser mencionados como outros importantes obstácu-los. 4 Além disso, o número possível de compostos com propriedades fármaco-similar (drug-like) 5 é várias ordens de magnitude maior do que o número de compostos que pode ser analisado nos processos de HTS. Portanto, o planejamento das bases de dados de compostos é essencial, sendo que fatores como propriedades moleculares e físico-químicas, ou ainda a diversidade química, devem ser considerados. [6][7][8] Com os notáveis avanços da biologia estrutural e a disponibilidade de recursos computacionais de alto desempenho, a VS surgiu como importante alternativa à HTS. A VS é um método in silico ("computacional") empre...

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“…The study of the molecular biology of cancer has identified several proteins which have potential as targets for new anticancer drugs (Sebolt-Leopold and English, 2006) and, in some cases, laboratory preclinical experiments have provided support that has encouraged the development of drugs directed against these systems. These new agents produce a more selective effect on these cells as they are directed, in principle, specifically to the molecular changes which distinguish cancer cells from normal cells thereby reducing toxicity to normal tissues (Benson et al, 2006). A few drugs to these targets have been evaluated by clinical trials, and a fraction of these have received regulatory approval for use in certain groups of cancer patients (Garber, 2006).…”

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confidence: 99%

“…A particular class of targets, which have proved to be of value are the proteins involved in signal transduction (Benson et al, 2006). The family of signal transduction proteins that has received the most attention to date are the Epidermal Growth Factor Receptor (EGFR) family, most likely as several of its members are manifestly involved in stimulating tumour growth and concepts of drug action are clear (Yarden and Sliwkowski, 2001;Mosesson and Yarden, 2004;Warren and Landgraf, 2006).…”

mentioning

confidence: 99%

Proteomic identification of secreted proteins as surrogate markers for signal transduction inhibitor activity

McClelland

Gullick

2007

Br J Cancer

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Epidermal growth factor receptor is a potential target for cancer treatment and new small-molecule tyrosine kinase inhibitor drugs have been designed to inhibit its activity. In this work we identify potential surrogate markers of drug activity using a proteomic analysis. Two-dimensional electrophoresis was optimised to compare expression patterns of proteins secreted from the cancer cell lines A431 and A549 treated with Gefitinib (Iressa) vs untreated or vehicle-only-treated samples. Upregulated or downregulated proteins were detected using Phoretix 2D image analysis software. Several proteins were then identified using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. In one case, upregulation of Protein Disulphide Isomerase in response to Gefitinib was confirmed by Western blot analysis, and the response was shown to be concentration dependent. The identification of surrogate markers may be of use for the evaluation of new drugs, in preclinical models, in clinical trials and in the therapy of individual patients to give optimal biological drug doses.

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Validating cancer drug targets

Cited by 146 publications

References 49 publications

Targeting Fanconi Anemia/BRCA2 Pathway Defects in Cancer: The Significance of Preclinical Pharmacogenomic Models

Targeting Fanconi Anemia/BRCA2 Pathway Defects in Cancer: The Significance of Preclinical Pharmacogenomic Models

Integração das técnicas de triagem virtual e triagem biológica automatizada em alta escala: oportunidades e desafios em P&D de fármacos

Proteomic identification of secreted proteins as surrogate markers for signal transduction inhibitor activity

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