CLM29 and CLM24, pyrazolopyrimidine derivatives, have antitumoral activity in vitro in anaplastic thyroid cancer, with or without BRAF mutation.

Abstract

We have studied the antitumor activity of two new "pyrazolo[3,4-d]pyrimidine" compounds (CLM29 and CLM24) that inhibit several targets (including the RET tyrosine kinase, epidermal growth factor receptor, vascular endothelial growth factor receptor, with an antiangiogenic effect) in primary anaplastic thyroid cancer (ATC) cell cultures and in the human cell line 8305C (undifferentiated thyroid cancer). The antitumor effect of CLM29 and CLM24 was tested in: nine primary ATC cultures obtained from patients at the time of surgery at the concentrations of 1, 5, 10, 30, 50µM; in 8305C cells at 1, 5, 10, 30, 50µM for CLM29, and 0.001, 0.01, 0.1, 1, 10, 100µM for CLM24. CLM29, and CLM24 significantly inhibited the proliferation of 8305C cells. A significant reduction of proliferation with CLM29 and CLM24 in ATC cells (P<0.01, for both, ANOVA) was shown. CLM29 and CLM24 increased the percentage of apoptotic ATC cells dose-dependently (P<0.001, ANOVA). The (V600E) BRAF mutation was observed in three ATCs; the results about the inhibition of proliferation by CLM29 and CLM24, obtained in ATC from tumors with (V600E) BRAF mutation were similar to those from tumors without BRAF mutation. CLM29 inhibited migration and invasion (P<0.01) of primary ATC cells, while CLM24had no significant effect. The antitumor activity of two new "pyrazolo[3,4-d]pyrimidine" compounds (CLM24, CLM29) in vitro in ATC, independent from BRAF mutation, has been shown, allowing a future clinical evaluation.