Rearranged during transfection (RET), a
receptor tyrosine kinase, is activated by
glial cell line-derived neurotrophic factor family
ligands. Chromosomal rearrangement or point mutations in RET are observed in patients with papillary thyroid and medullary
thyroid carcinomas. Oncogenic alteration of RET results in constitutive activation of RET activity. Therefore, inhibiting RET activity has become a target in
thyroid cancer therapy. Here, the anti-
tumor activity of a novel RET inhibitor was characterized in medullary
thyroid carcinoma cells. The
indirubin derivative LDD-2633 was tested for RET
kinase inhibitory activity. In vitro, LDD-2633 showed potent inhibition of RET
kinase activity, with an IC50 of 4.42 nM. The growth of TT
thyroid carcinoma cells harboring an RET mutation was suppressed by LDD-2633 treatment via the proliferation suppression and the induction of apoptosis. The effects of LDD-2633 on the RET signaling pathway were examined; LDD-2633 inhibited the phosphorylation of the RET
protein and the downstream molecules Shc and ERK1/2.
Oral administration of 20 or 40 mg/kg of LDD-2633 induced dose-dependent suppression of TT cell xenograft
tumor growth. The in vivo and in vitro experimental results supported the potential use of LDD-2633 as an anticancer drug for
thyroid cancers.