Challenging clinically unresponsive medullary thyroid cancer: Discovery and pharmacological activity of novel RET inhibitors.
Eur J Med Chem
; 150: 491-505, 2018 Apr 25.
Article
em En
| MEDLINE
| ID: mdl-29549836
ABSTRACT
It is now known that "gain of function" mutations of RET (REarranged during Transfection) kinase are specific and key oncogenic events in the onset of thyroid gland cancers such as the Medullary Thyroid Carcinoma (MTC). Although a number of RET inhibitors exist and are capable of inhibiting RET variants, in which mutations are outside the enzyme active site, the majority becomes dramatically ineffective when mutations are within the protein active site (V804L and V804M). Pursuing a receptor-based virtual screening against the kinase domain of RET, we found that compound 5 is able to inhibit efficiently both wild type and V804L mutant RET. Compound 5 was able to significantly reduce proliferation of both commercially available TT cell lines and surgical thyroid tissues obtained from patients with MTC and displayed a suitable drug-like profile, thus standing out as a promising candidate for further development towards the treatment of clinically unresponsive MTC.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Glândula Tireoide
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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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Proteínas Proto-Oncogênicas c-ret
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Descoberta de Drogas
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Itália