The human EGF receptor (HER) 2 receptor tyrosine kinase is a survival factor for human cardiomyocytes. It plays an essential role in cardiac development during embryogenesis. Here, we will introduce a potent small molecule HER2/EGFR tyrosine kinase inhibitor, GW2974. It activates AMPK and its downstream substrates, and stimulates fatty acid oxidation, which in turn increases ATP production in HER2-expressing human cardiomyocytes, protecting against apoptosis induced by TNFα, a known cytokine detected in cardiac failure.
GW2974 is a potent small molecule HER2/EGFR tyrosine kinase inhibitor
GW2974 is a potent dual inhibitor of EGFR and HER2 with IC50 value of 0.007 μM and 0.016 μM, respectively. Meanwhile, GW2974 demonstrates in vitro inhibition of the EGFR and HER2 and inhibits the growth of tumor cell. Firstly, GW2974 (0.5-50 μM, 3 h) has an obvious cytotoxicity appeared at 10 μM or above and inhibits cell proliferation of U87MG and U251MG cells at 0.5-5 μM after 24 h treatment. Secondly, GW2974 (0.5-5 μM, 24 h) has a dose-related role in GBM cell invasion and migration. Thirdly, GW2974 (0.001-100 μM, 24 h) inhibits BT474, HN5, N87 cells growth.
In vivo, GW2974 (30 mg/kg, 100 mg/kg for oral gavage, once a day) inhibits GBM growth, invasion, and angiogenesis in dose of 30 mg/kg. But GW2974 (100 mg/kg) abrogates the inhibitory effect on tumor invasion in GBM xenograft mice model. Furthermore, GW2974 (10 mg/kg, 30 mg/kg, oral gavage, twice a day) inhibits the growth of tumor in CD-1 nude mice (HN5) and C.B-17 SCID mice (BT474) models in a dosed dependent manner.
In a word, GW2974 is an EGFR/HER2 Inhibitor and can be used for glioblastoma multiforme (GBM) disease research.