Tyrosine kinase inhibitors (TKIs) are molecules that compete with ATP on tyrosine kinase
receptors (TKRs), blocking tyrosine kinase (TK) activation and then oncogenic pathways; they have
been studied, and some of them are right approved for the treatment of many types of cancer. Among
TKIs, one of the most explored chemical template is the pyrazolo[3,4-d]pyrimidine (PP) heterocyclic
core, which proved to be a useful scaffold for the obtainment of effective compounds. Actually,
derivatives belonging to this structural class show a large spectrum of activity, thus standing out as multi-target agents.
Different PP compounds have been shown to act as: a) ABL inhibitors and antiproliferative agents against human
leukemia cell lines; b) Src kinase inhibitors in neuroblastoma, medulloblastoma and osteosarcoma; c) Phospholipase D
inhibitors in different neoplasias; d) Urokinase plasminogen activator inhibitors, in breast cancer. In thyroid cancer (TC),
PP1 and PP2 (inhibitors of RET, Hck, lck, and fynT kinases, and a good inhibitor of c-Src and platelet-derived growth
factor receptor) showed antineoplastic actvity in human papillary TC cell lines that carry spontaneous RET/PTC1
rearrangements. More recently, new derivatives, (R)-1-phenethyl-N-(1-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-
amine, namely, CLM3 and CLM29, have been demonstrated to exert a multiple signal transduction inhibition (including
the RET-TK, BRAF, EGFR, and with antiangiogenic activity), showing antineoplastic activity, in vitro and in vivo, in
papillary dedifferentiated, medullary and anaplastic TC. These data have shown the antineoplastic activity of PP in
different neoplasias, opening the way to a future clinical evaluation in human cancers.