AST-487 is a RET kinase inhibitor with IC50 of 880 nM, inhibits RET autophosphorylation and activation of downstream effectors, also inhibits Flt-3 with IC50 of 520 nM. AST487 also inhibits RET,KDR,c-KIT,and c-ABL kinase with IC50 values below 1 μM.
The RET kinase has emerged as a promising target for the therapy of medullary thyroid cancers (MTC) and of a subset of papillary thyroid cancers[3]. AST-487, a N, N′-diphenyl urea with an IC50 of 0.88 μM on RET kinase, inhibited RET autophosphorylation and activation of downstream effectors, and potently inhibited the growth of human thyroid cancer cell lines with activating mutations of RET but not of lines without RET mutations. AST-487 induced a dose-dependent growth inhibition of xenografts of NIH3T3 cells expressing oncogenic RET, and of the MTC cell line TT in nude mice. Additionally, AST-487 inhibited calcitonin gene expression in vitro in TT cells, in part, through decreased gene transcription[3]. After a single oral administration of 15 mg/kg of AST-487 to OF1 mice, a mean peak plasma level (Cmax) of 0.505±0.078 μM SE is achieved after 0.5 h. Similar levels of AST 487 are found in the plasma of mice up to 6 h after oral administration, with a Clast of 21±4 nM at 24 h[3].
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