Mubritinib

Mubritinib, also known as TAK-165, is a protein kinase inhibitor which was under development by Takeda for the treatment of cancer. It completed phase I clinical trials (may be discontinued since 2008) . Mubritinib (TAK 165) is a potent EGFR, HER2 and p34cdc2 inhibitor with IC50 of 6 nM and 0.2 μM, respectively. Mubritinib (TAK 165) also inhibits p33cdk2 and p33cdk5. Mubritinib (TAK 165) displays > 4000-fold selectivity over EGFR, FGFR, PDGFR, JAK1 and Src. Mubritinib (TAK 165) exhibits potent antiproliferative effects in ErbB2-overexpressing cancer cell lines (IC50 = 5 nM in BT474 breast cancer cells) and significantly inhibits bladder, breast and prostate cancer xenograft growth in vivo. (In Vitro) :Mubritinib (TAK-165) specifically inhibits HER2 tyrosine kinase with an IC50 6 nM and does not inhibit other types tyrosine kinase up to 25 000 nM. Mubritinib inhibits HER2 phosphorylation and its down-stream Akt and MAPK in HER2 strongly expressing cells (BT474 breast cancer cell line) . Mubritinib sensitivity depends on HER2 levels of each cell line. Especially, BT474 cells which over-express HER2 strongly is highly sensitive (IC50=0.005 μM) and PC-3 cells which express HER2 very weakly is less sensitive (IC50=4.62 μM) . But, HT1376 and ACHN cells that over-expressed EGFR showed high IC50 (IC50>25 μM) . (In Vivo) :In the xenograft model, treatment with Mubritinib (TAK-165) significantly inhibits growth of UMUC-3, ACHN, and LN-REC4. The antitumor effect after 14 days treatment are 22.9%, 26.0%, and 26.5% in UMUC3, ACHN and LN-REC4, respectively.