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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)

Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare "L. Califano" (F.C., D.V., T.G., M.D.C., R.M.M., A.F., M.S.), Università "Federico II", 80131 Naples; and Dipartimento di Oncologia (F.B.), Università degli Studi di Pisa, 56126 Pisa, Italy

Address all correspondence and requests for reprints to: Massimo Santoro, Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Facoltà di Medicina e Chirurgia, via S. Pansini 5, 80131 Naples, Italy. E-mail: masantor{at}unina.it.

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 IC₅₀ 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.

Footnotes

This study was supported by the Associazione Italiana per la Ricerca sul Cancro, by the Italian Ministero per l’Istruzione, Università e Ricerca Scientifica, and by the Italian Ministero della Salute.

Abbreviations: BrdU, Bromodeoxyuridine; DMSO, dimethylsulfoxide; GST, glutathione-S-transferase; MEN, multiple endocrine neoplasia; MTC, medullary thyroid carcinoma; poly-GT, poly(L-glutamic acid-L-tyrosine; PP1, pyrazolopyrimidine; PP2, 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine); PTC, papillary thyroid carcinoma; TK, tyrosine kinase.

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