AST 487

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. IC50 & Target: IC50: 880 nM (RET), 170 nM (KDR), 790 nM (Flt-4), 500 nM (c-Kit), 520 nM (Flt-3), 20 nM (Abl)^[1] In Vitro: A number of other kinases are also similarly inhibited by AST 487 (NVP-AST487) in the in vitro kinase assays, including KDR (IC₅₀=170 nM), Flt-4 (IC₅₀=790 nM), Flt-3 (IC₅₀=520 nM), c-Kit (IC₅₀=500 nM), and c-Abl (IC₅₀=20 nM). AST 487 potently inhibits the growth of human thyroid cancer cell lines with activating mutations of RET but not of lines without RET mutations. Both GDNF/GFRα1 and persephin-induced calcitonin mRNA are markedly inhibited by coincubation with 100 nM of AST 487 in MTC-M cells^[1]. AST 487 is a novel, mutant FLT3 inhibitor. AST 487 is tested in biochemical assays for inhibition of Flt-3 kinase activity. The K_i is determined to be 0.12 μM. Besides Flt-3, NVP-AST487 inhibits RET, KDR, c-Kit, and c-Abl kinase with IC₅₀ values below 1 μM. Treatment of FLT3-ITD-Ba/F3 cells and D835Y-Ba/F3 cells with AST 487 potently inhibits cellular proliferation (IC₅₀<5 nM). AST 487 treatment of FLT3-ITD-Ba/F3 cells with 0.01 μM AST 487 results in complete cell killing compare with approximately 50% killing of AML patient samples at the same concentration^[2]. In Vivo: After a single oral administration of 15 mg/kg of AST 487 to OF1 mice, a mean peak plasma level (C_max) 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 C_last of 21±4 nM at 24 h. The oral bioavailability is calculated to be 9.7% with a t_1/2 terminal elimination of 1.5 h^[1].