AST 487

A number of other kinases are also similarly inhibited by AST 487 (NVP-AST487) in the in vitro kinase assays, including KDR (IC ₅₀ =170 nM), Flt-4 (IC ₅₀ =790 nM), Flt-3 (IC ₅₀ =520 nM), c-Kit (IC ₅₀ =500 nM), and c-Abl (IC ₅₀ =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. 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 IC ₅₀ values below 1 μM. Treatment of FLT3-ITD-Ba/F3 cells and D835Y-Ba/F3 cells with AST 487 potently inhibits cellular proliferation (IC ₅₀ <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.

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.