Structure-Based Optimization of Tyrosine Kinase Inhibitor CLM3. Design, Synthesis, Functional Evaluation, and Molecular Modeling Studies.
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- 作者：Stefania Sartini ; Vito Coviello ; Agostino Bruno ; Valeria La Pietra ; Luciana Marinelli ; Francesca Simorini ; Sabrina Taliani ; Silvia Salerno ; Anna Maria Marini ; Anna Fioravanti ; Paola Orlandi ; Alessandro Antonelli ; Federico Da Settimo ; Ettore Novellino ; Guido Bocci ; Concettina La Motta
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：February 27, 2014
- 年：2014
- 卷：57
- 期：4
- 页码：1225-1235
- 全文大小：504K
- 年卷期：v.57,no.4(February 27, 2014)
- ISSN：1520-4804
文摘
Recent advances in the knowledge of thyroid carcinomas development identified receptor tyrosine kinases, like VEGFR2 and RET, as viable and promising targets. Accordingly, their inhibition is emerging as the major therapeutic strategy to treat these pathologies. In this study we describe the synthesis and the functional evaluation of three different series of 4-substituted pyrazolo[3,4-d]pyrimidine derivatives, 8a鈥?b>g, 9a鈥?b>g, and 10a鈥?b>g, designed exploiting a structure-based optimization of the previously developed inhibitor CLM3. Compared to the lead, the novel compounds markedly improved both their inhibitory profile against the target proteins, VEGFR2 and RET, and their antiproliferative efficacy against the medullary thyroid cancer cell line TT. Significantly, compounds 8b, 9c, and 10c proved to block the kinase activity of the mutant RETV804L, which still lacks effective inhibitors.