CAL-130
CAL-130 用途与合成方法
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p110δ 1.3 nM (IC 50 ) |
p110γ 6.1 nM (IC 50 ) |
p110β 56 nM (IC 50 ) |
p110α 115 nM (IC 50 ) |
CAL-130 preferentially inhibits the function of both p110γ and p110δ catalytic domains. IC 50 values of CAL-130 are 1.3 and 6.1 nM for p110δ and p110γ, respectively, as compared to 115 and 56 nM for p110α and p110β. CAL-130 does not inhibit additional intracellular signaling pathways (i.e., p38 MAPK or insulin receptor tyrosine kinase) that are critical for general cell function and survival.
The clinical significance of interfering with the combined activities of PI3Kγ and PI3Kδ is determined by administering CAL-130 to Lck/Pten fl/fl mice with established T cell acute lymphoblastic leukemia (T-ALL). Candidate animals for survival studies are ill appearing, have a white blood cell (WBC) count above 45,000 μL -1 , evidence of blasts on peripheral smear, and a majority of circulation cells (>75%) staining double positive for Thy1.2 and Ki-67. Mice receive an oral dose (10 mg/kg) of CAL-130 every 8 hr for a period of 7 days and are then followed until moribund. Despite the limited duration of therapy, CAL-130 is highly effective in extending the median survival for treated animals to 45 days as compared 7.5 days for the control group.
