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Bioorg Med Chem Lett ; 20(17): 5027-30, 2010 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-20675137


Pyrrolidine, pyrrolidinone, carbocyclic, and acyclic groups were used as isosteric proline replacements in a series of insulin-like growth factor I receptor kinase/insulin receptor kinase inhibitors. Examples that were similar in potency to proline-containing reference compounds were shown to project a key fluoropyridine amide into a common space, while less potent compounds were not able to do so for reasons of stereochemistry or structural rigidity.

Prolina/química , Inibidores de Proteínas Quinases/química , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor de Insulina/antagonistas & inibidores , Triazinas/química , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacologia , Triazinas/farmacologia
Bioorg Med Chem Lett ; 20(5): 1744-8, 2010 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-20153189
Cancer Res ; 65(9): 3781-7, 2005 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-15867374


The insulin-like growth factor I receptor (IGF-IR) is a transmembrane tyrosine kinase that is essential to growth and development and also thought to provide a survival signal for the maintenance of the transformed phenotype. There has been increasing interest in further understanding the role of IGF-I signaling in cancer and in developing receptor antagonists for therapeutic application. We describe herein a novel animal model that involves transgenic expression of a fusion receptor that is constitutively activated by homodimerization. Transgenic mice that expressed the activated receptor showed aberrant development of the mammary glands and developed salivary and mammary adenocarcinomas as early as 8 weeks of age. Xenograft tumors and a cell line were derived from the transgenic animals and are sensitive to inhibition by a novel small-molecule inhibitor of the IGF-IR kinase. This new model should provide new opportunities for further understanding how aberrant IGF-IR signaling leads to tumorigenesis and for optimizing novel antagonists of the receptor kinase.

Adenocarcinoma/genética , Transformação Celular Neoplásica/genética , Neoplasias Mamárias Experimentais/genética , Receptor IGF Tipo 1/biossíntese , Neoplasias das Glândulas Salivares/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Antígenos CD8/biossíntese , Antígenos CD8/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Feminino , Humanos , Neoplasias Mamárias Experimentais/enzimologia , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Camundongos Transgênicos , Transplante de Neoplasias , Gravidez , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Neoplasias das Glândulas Salivares/enzimologia , Neoplasias das Glândulas Salivares/patologia , Transfecção , Transgenes/genética , Transplante Heterólogo