Development of anti-angiogenic tyrosine kinases inhibitors: molecular structures and binding modes.
Cancer Chemother Pharmacol
; 77(5): 905-26, 2016 05.
Article
em En
| MEDLINE
| ID: mdl-26781310
ABSTRACT
PURPOSE:
Since the hypothesis that solid tumors cause angiogenesis by secreting pro-angiogenic factors was introduced, research on angiogenesis has proceeded continuously. Development of inhibitors targeting the angiogenic tyrosine kinases, to block downstream signal transduction pathways, has become an important approach to cancer therapy. Our goal was to study the development and mechanism of anti-angiogenic tyrosine kinases inhibitors.METHODS:
We researched data on discovery of the inhibitors and their binding modes using the PubMed, Web of Science, Food and Drug Administration (FDA), and Clinical Trials Web sites.RESULTS:
In the last decade, many small molecule inhibitors targeting angiogenesis have been designed and synthesized with many now entering the clinic or gaining FDA approval. Advances in understanding regulatory mechanisms of angiogenesis have enabled development of these drugs. The development of inhibitors up to Phase 3 clinical trials and, for many, FDA approval has helped leading to the discovery of additional compounds. The structures, activities, and binding modes of these inhibitors are discussed in this review.CONCLUSIONS:
Though the angiogenesis inhibitors have different chemical structures, they share similar binding modes. Their interactions with the hinge region of receptor tyrosine kinases (RTKs) are critical to their effectiveness as inhibitors. In addition, as we review here, different drugs, when bound, induce different conformations of RTKs.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Tirosina Quinases
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Receptores Proteína Tirosina Quinases
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Inibidores da Angiogênese
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Descoberta de Drogas
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Neovascularização Patológica
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article