Background:

TAK-285 is a potent inhibitor of HER2 and EGFR with IC50 value of 17 nM and 23 nM, respectively [1].

EGFR (epidermal growth factor receptor) and HER2 are members of ErbB family of receptors and play an important role in stimulating its intrinsic intracellular protein-tyrosine kinase activity. It has been shown that the over-expressions of HER-2 and EGFR are correlated with a variety of cancers and thus be regarded as promising target in clinic [2].

TAK-285 is a selective HER2 and EGFR inhibitor and has a different selectivity with the reported HER inhibitor AST-6. When tested with a panel of breast cancer cell lines, cells over-expressed HER2 (BT-474, NCI-N87, SK-BR-3, Calu-3, and MDA-MB-453) or EGFR (A-431) were more sensitive to TAK-285 treatment while normal expressed cell line (MRC-5) was less sensitive [1]. [3].

In rat model with 4-1ST (over-express HER2) or A-431 (over-express EGFR) subcutaneous xenograft, administration of TAK-285 caused significant reduction of tumor growth with T/C values of 14% and 13%, respectively, at a dose of 12.5 mg/kg, compared with control group [1]. In a panel of human breast cancer cell lines expressing EGFR, HER2, HER3, and HER4, administration of TAK-285 significantly inhibited cell proliferation in a dose-dependent manner with IC50 values range from 0.011 to 17 μM [3].

It is also reported that TAK-285 inhibited Akt and MAPK phosphorylation with IC50 value of 0.015 μM and<0.0063 μM, respectively [1].

参考文献:
[1].  Nakayama, A., et al., Antitumor Activity of TAK-285, an Investigational, Non-Pgp Substrate HER2/EGFR Kinase Inhibitor, in Cultured Tumor Cells, Mouse and Rat Xenograft Tumors, and in an HER2-Positive Brain Metastasis Model. J Cancer, 2013. 4(7): p. 557-65.
[2].  Lyakhov, I., et al., HER2- and EGFR-specific affiprobes: novel recombinant optical probes for cell imaging. Chembiochem, 2010. 11(3): p. 345-50.
[3].   Takagi, S., et al., HER2 and HER3 cooperatively regulate cancer cell growth and determine sensitivity to the novel investigational EGFR/HER2 kinase inhibitor TAK-285. Oncoscience, 2014. 1(3): p. 196-204.