AD80, a multikinase inhibitor, shows strong activity against human RET (c-RET), BRAF, S6K, and SRC but were much less active than either AD57 or AD58 against mTOR. The IC50 value for RET is 4 nM.
AD80 prevents the phosphorylation of RET as well as of extracellular signa-regulated kinase (ERK), AKT, and S6K at low nanomolar concentrations in kinesin family member 5B (KIF5B)-RET-expressing Ba/F3 cells. Treatment with AD80 results in up-regulation of genes that are typically repressed by active KRAS. On the contrary, genes that are activated by KRAS were down-regulated[1]. On the basis of in vitro human kinase profiles, AD80 and AD81 inhibit RET, RAF, SRC and S6K, with greatly reduced mTOR activity relative to AD57 and AD58. AD80 inhibits proliferation of MZ-CRC-1 and TT thyroid cancer cells in culture, probably through the induction of apoptosis[2].
AD80 is a highly potent RET inhibitor with a favorable pharmacokinetic profile in clinically relevant RET fusion-driven tumor models. AD80 potently shrinks RET-rearranged tumors in patient-derived xenografts. A pronounced reduction in phosphorylation of RET as well as AKT and ERK in tumors treated with AD80 (25 mg/kg) is observed but not in tumors treated with cabozantinib or vandetanib[1].
[1] Plenker D, et al. Sci Transl Med. 2017, 9(394). pii: eaah6144. [2] Dar AC, et al. Nature. 2012, 486(7401):80-4.