Cancer

In vitro, cell culture, mouse and rat studies identified an inhibitor of internal tandem duplication (ITD)-mutant FLT3 that could help treat AML. Chemical synthesis and cell-based binding assays of analogs of two inhibitors of FLT3 and other receptor tyrosine kinases -- Nexavar sorafenib and a tool compound inhibitor -- yielded a phenylacetamide-based compound that inhibited proliferation of mouse pro B cells expressing ITD-mutant FLT3 with an IC₅₀ of 32 nM. In mouse pro B cells expressing four other ITD mutations in FLT3, the compound inhibited proliferation with IC₅₀ values of 32-85 nM. In three human AML cell lines expressing ITD-mutant FLT3, the compound inhibited growth with IC₅₀ values of 284-466 nM. In a xenograft mouse model of AML expressing ITD-mutant FLT3, the compound decreased tumor growth compared with vehicle. In rats, the compound had a plasma half-life of 1.3 hours. Next steps could include optimization and testing of the compound in models of AML expressing ITD-mutant FLT3.

Amgen Inc. and Bayer AG market Nexavar for liver, renal and thyroid cancers and have the product in Phase III testing as an adjuvant for liver cancer...