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 this kind of 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-g, 9a-g, and 10a-g, designed exploiting a structure-based optimization of the previously developed inhibitors 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 also the kinase activity of the mutant RETV804L, which still lacks effective inhibitors.