Integrated computational and Drosophila cancer model platform captures previously unappreciated chemicals perturbing a kinase network.
PLoS Comput Biol
; 15(4): e1006878, 2019 04.
Article
em En
| MEDLINE
| ID: mdl-31026276
ABSTRACT
Drosophila provides an inexpensive and quantitative platform for measuring whole animal drug response. A complementary approach is virtual screening, where chemical libraries can be efficiently screened against protein target(s). Here, we present a unique discovery platform integrating structure-based modeling with Drosophila biology and organic synthesis. We demonstrate this platform by developing chemicals targeting a Drosophila model of Medullary Thyroid Cancer (MTC) characterized by a transformation network activated by oncogenic dRetM955T. Structural models for kinases relevant to MTC were generated for virtual screening to identify unique preliminary hits that suppressed dRetM955T-induced transformation. We then combined features from our hits with those of known inhibitors to create a 'hybrid' molecule with improved suppression of dRetM955T transformation. Our platform provides a framework to efficiently explore novel kinase inhibitors outside of explored inhibitor chemical space that are effective in inhibiting cancer networks while minimizing whole body toxicity.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Quinases
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Neoplasias da Glândula Tireoide
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Carcinoma Neuroendócrino
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Inibidores de Proteínas Quinases
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Avaliação Pré-Clínica de Medicamentos
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Antineoplásicos
Idioma:
En
Revista:
PLoS Comput Biol
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos