Structure-Based Optimization of Tyrosine Kinase Inhibitor <b>CLM3</b>. Design, Synthesis, Functional Evaluation, and Molecular Modeling Studies.

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-<i>d</i>]­pyrimidine derivatives, <b>8a</b>–<b>g</b>, <b>9a</b>–<b>g</b>, and <b>10a</b>–<b>g</b>, designed exploiting a structure-based optimization of the previously developed inhibitor <b>CLM3</b>. 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 <b>8b</b>, <b>9c</b>, and <b>10c</b> proved to block the kinase activity of the mutant RET^V804L, which still lacks effective inhibitors