tcsc0227 BMS 777607

BMS 777607 is a Met-related inhibitor for c-Met, Axl, Ron and Tyro3 with IC₅₀s of 3.9 nM, 1.1 nM, 1.8 nM and 4.3 nM, respectively, and 40-fold more selective for Met-related targets than Lck, VEGFR-2, and TrkA/B, with more than 500-fold greater selectivity versus all other receptor and non receptor kinases.

IC50 & Target: IC50: 3.9 nM (c-Met), 1.1 nM (Axl), 1.8 nM (Ron), 4.3 nM (Tyro3)

In Vitro: BMS 777607 is a selective ATP-competitive Met kinase inhibitor which potently blocks the autophosphorylation of c-Met with IC₅₀ of 20 nM in GTL-16 cell lysates, and demonstrates selective inhibition of proliferation in Met-driven tumor cell lines, such as GTL-16 cell line, H1993 and U87^[1]. BMS 777607 inhibits hepatocyte growth factor (HGF)-triggered c-Met autophosphorylation with IC₅₀ of < 1 nM in PC-3 and DU145 prostate cancer cells. BMS 777607 has little effect on tumor cell growth, but exhibits inhibitory effect on HGF-induced cell scattering in PC-3 and DU145 cells, with almost complete inhibition at 0.5 μM. BMS 777607 also suppresses stimulated cell migration and invasion in a dose-dependent fashion (IC₅₀ < 0.1 μM) in both cell lines^[2]. Application of BMS 777607 (appr 10 μM) to the highly metastatic murine KHT cells for 2 hours potently eliminates basal levels of autophosphorylated c-Met with IC₅₀ of 10 nM without affecting the total c-Met, leading to dose-dependent inhibition of phosphorylation of downstream signaling molecules including ERK, Akt, p70S6K and S6. Treatment with BMS 777607 (appr 1 μM) for 24 hours potently inhibits the KHT cell scatter, motility and invasion at doses in the nanomolar range which consists with MET gene knockdown, and modestly affects cell proliferation and colony formation^[3].



In Vivo: Oral administration of BMS 777607 (6.25-50 mg/kg) significantly reduces tumor volumes of the GTL-16 human tumor xenografts in athymic mice with no observed toxicity^[1]. Administration of BMS 777607 (25 mg/kg/day) decreases the number of KHT lung tumor nodules (28.3%), improves the morphological hemorrhage, and significantly impairs the metastatic phenotype in the 6-8 week-old female C3H/HeJ mice injected with rodent fibrosarcoma KHT cells without apparent systemic toxicity compared to the control treatment. A low dose of BMS 777607 (10 mg/kg) also offers a mild but not significant inhibition of lung nodule formation compared to the vehicle control^[3].