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)
Open Access
- 1 April 2003
- journal article
- other
- Published by The Endocrine Society in Journal of Clinical Endocrinology & Metabolism
- Vol. 88 (4) , 1897-1902
- https://doi.org/10.1210/jc.2002-021278
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.Keywords
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