title: Efficient inhibition of RET/papillary thyroid carcinoma oncogenic kinases by 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2).
abstract: Inappropriate activation of the RET receptor tyrosine kinase causes development of papillary and medullary thyroid cancer. We have previously shown that pyrazolopyrimidine is a potent inhibitor of the RET kinase. Here, we show that 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) (PP2), another pyrazolopyrimidine, blocks the enzymatic activity of the isolated RET kinase and RET/PTC1 oncoprotein at IC(50) in the nanomolar range. PP2 blocked in vivo phosphorylation and signaling of the RET/PTC1 oncoprotein. PP2 prevented serum-independent growth of RET/PTC1-transformed NIH3T3 fibroblasts and of TPC1 and FB2, two human papillary thyroid carcinoma cell lines that carry spontaneous RET/PTC1 rearrangements. Finally, PP2 blocked invasion of type I collagen matrix by TPC1 cells. Thus, pyrazolopirimidines hold promise for the treatment of human cancers sustaining oncogenic activation of RET.
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare L. Califano, Università Federico II, 80131 Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Carlomagno
authors.forename: Donata
authors.initials: D
authors.lastname: Vitagliano
authors.forename: Teresa
authors.initials: T
authors.lastname: Guida
authors.forename: Fulvio
authors.initials: F
authors.lastname: Basolo
authors.forename: Maria Domenica
authors.initials: MD
authors.lastname: Castellone
authors.forename: Rosa Marina
authors.initials: RM
authors.lastname: Melillo
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
authors.forename: Massimo
authors.initials: M
authors.lastname: Santoro
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002291:Carcinoma, Papillary / Q000201:enzymology; D002461:Cell Line, Transformed; D029721:Drosophila Proteins; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015321:Gene Rearrangement; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D011743:Pyrimidines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000201:enzymology* / Q000473:pathology; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C412373:AG 1879; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse; D020928:Mitogen-Activated Protein Kinases