title: Pyrazolopyrimidine Derivatives as Antineoplastic Agents: with a Special Focus on Thyroid Cancer.
abstract: 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.
authors.forename: Silvia Martina
authors.initials: SM
authors.lastname: Ferrari
authors.forename: Concettina
authors.initials: C
authors.lastname: La Motta
authors.forename: Stefania
authors.initials: S
authors.lastname: Sartini
authors.forename: Enke
authors.initials: E
authors.lastname: Baldini
authors.forename: Gabriele
authors.initials: G
authors.lastname: Materazzi
authors.forename: Ugo
authors.initials: U
authors.lastname: Politti
authors.forename: Ilaria
authors.initials: I
authors.lastname: Ruffilli
authors.forename: Salvatore
authors.initials: S
authors.lastname: Ulisse
authors.forename: Paolo
authors.initials: P
authors.lastname: Miccoli
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Savi, 10, 56126, Pisa, Italy. alessandro.antonelli@med.unipi.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Antonelli
authors.forename: Poupak
authors.initials: P
authors.lastname: Fallahi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D017382:Reactive Oxygen Species; C000606692:pyrazolylpyrimidine; D011505:Protein-Tyrosine Kinases