The REarranged during Transfection (RET) receptor tyrosine kinase (RTK) regulates key aspects of cellular proliferation and survival by regulating the activity of the mitogen- activated protein kinase (MAPK) and PI3K/Akt signaling pathways. The RET tyrosine kinase receptor has emerged as a target in thyroid and endocrine resistant breast cancer.

A study from John P Alao discovered and identified a RET kinase selective inhibitor, SPP-86. SPP-86 is a potent and selective cell permeable inhibitor of RET tyrosine kinase, with an IC50 of 8 nM.

In the study, the authors used several human cancer cells to carry out a series in vitro experiments.

Firstly, the authors found that SPP-86 effectively inhibits ERK1/2 phosphorylation in TPC1 cells expressing the RET/PTC1 rearrangement at a concentration of 1 μM. Inversely, the compound had no effect on ERK1/2 phosphorylation in 8505C or C643 cells.

Furthermore, in human breast cancer cell lines, estrogen deprived and serum starved MCF7 cells were exposed to 10 ng/mL GDNF in the absence or presence of increasing does of SPP-86. In these experiments, SPP-86 effectively inhibited GDNF/RET-induced ERα phosphorylation at a concentration of 0.1 μM. SPP-86 with the concentration of 1-10 μM, reduced ERα phosphorylation even below baseline levels. In addition, exposure of MCF7 cells to SPP86 was associated with a moderate decrease in ERα levels in these experiments.

During the study, we can know that SPP86, a selective inhibitor towards RET on cancer cell proliferation. SPP86 is cell permeable, potently inhibits RET activity in vitro and in vivo, and exhibits a unique selectivity profile that differs from previously reported inhibitors with activity towards this kinase.

Alao JP, et al. Selective inhibition of RET mediated cell proliferation in vitro by the kinase inhibitor SPP86. BMC Cancer. 2014 Nov 20;14:853.