Chk2 kinase is a key mediator of the DNA damage checkpoint. BML-277 is a Chk2 inhibitor with an IC50 value of 15nM. It rescued CD4+ and CD8+ cells from radiation-induced apoptosis in a dose-dependent manner with an EC50 of 3-7.6µM[2]. BML-277 at 1-10µM inhibited CHK2 phosphorylation at Thr68 at different time courses (30min, 1h, 2h, and 4h) in both Farage and SUDHL6 cells. Treatment of SUDHL4, SUDHL6, and Farage cells with 5μM BML-277 led to apoptosis of less than 30% cells. BML-277 at 1 and 5μM significantly diminished the physical interaction between ERK and CHK2 in Farage and SUDHL6 cells at 4h post-exposure. In SUDHL6, Farage, and OCI-LY3 cells, BML-277 at 1-10µM reduced CHK2 phosphorylation at Thr68 but increased ERK phosphorylation compared to the control cells. Intraperitoneal administration of BML-277 (1mg/kg) every other day for 20 days modestly inhibited tumor growth in mice bearing subcutaneous tumors of SUDHL6 cells compared to the vehicle-treated group. The combination treatment of BML-277 (1mg/kg) and ERK inhibitor (5mg/kg) for 20 days resulted in a significant reduction in Ki67 expression and tumor suppression in mice inoculated with SUDHL6 cells[3].
作用机制
BML-277 inhibits Chk2 in an ATP-competitive manner. The hydrogen bonding interactions are predicted to occur between the 5-amide group of the benzimidazole moiety and the backbone amide nitrogen and carbonyl group of MET 90[2].
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