TAK-285

Besides HER2 and EGFR, TAK-285 only exhibits potent inhibitory activity against HER4 with IC50 of 260 nM. TAK-285 slightly inhibits MEK1, MEK5, c-Met, Aurora B, Lck, CSK, and Lyn B with IC50 of 1.1-5.7 μM. TAK-285 displays potent in vitro antitumor efficacy in HER2-overexpressing BT-474 cells in a dose-dependent manner, and in vivo dose-dependent activity against BT-474 or 4-1ST xenografts in mice and rats. Like SYR127063, TAK-285 binds to the respective kinase in an ATP-competitive manner, which is confirmed by crystallographic data. TAK-285 binds to the inactive conformation of EGFR, and shows a similar binding mode with lapatinib in the active site. The mutations and shortened HER2 and EGFR do not significantly change the inhibitory activity of TAK-285. Given the substantial brain penetration of unbound TAK-285, TAK-285 might have the potential in the treatment of brain metastases of HER2 over-expressing metastatic breast cancer. In Phase I trails, TAK-285 is well tolerated, and rapid absorbed after oral dosing, with the plasma exposure at steady-state increased in a dose-proportional fashion for doses ranging from 50 to 300 mg b.i.d. TAK-285 leads to a partial response in one patient with parotid cancer receiving 300 mg b.i.d.