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AD80, a multikinase inhibitor, inhibits RET, RAF,SRCand S6K, with greatly reduced mTOR activity.

AD80 is a polypharmacological agent with an optimal balance of activity against Ret, Raf, Src, Tor and S6K that show high efficacy with very low toxicity. AD80 and AD81 inhibits RET, RAF, SRC and S6K, with greatly reduced mTOR activity relative to AD57 and AD58.AD80 is optimal for Ras–Erk pathway inhibition. AD80 inhibits proliferation of MZ-CRC-1 and TT thyroid cancer cells in culture, probably through the induction of apoptosis. Immunoblot analysis demonstrates potent downregulation of phosphorylated Ret and several downstream biomarkers within these cells. AD80 coordinately inhibits S6K1 together with the TAM family tyrosine kinase AXL.AD80 avoides S6K1 phosphorylation and mTOR co-association, resulting in durable suppression of S6K1-induced signaling and protein synthesis.

Oral administration of either AD80 or AD81 results in a notable 70-90% of animals developing to adulthood in Drosophila ptc>dRetmodel, a considerable improvement over the efficacy observed with AD57. AD80 also promotes enhanced tumour growth inhibition and reduces body-weight modulation relative to vandetanib in a mouse xenograft model. AD80 rescues 50% of mice transplanted with PTEN-deficient leukemia cells.

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