Checkpoint kinase 1 inhibitors for potentiation of DNA-damaging agents
A DNA damage agent and inhibitor technology, applied in the field of CHK1 inhibitors, can solve problems such as cancer cell death
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Embodiment 1
[0087] Female nude mice were subcutaneously inoculated with 5X10 in 1X PBS (100 μL) 6 HT-29 tumor cells. After 11 days, the mice were randomly divided into 3 groups with an average tumor volume of approximately 300 mm in each group 3 . Sorted animals were administered CPT11 (100 mg / kg; IP) for 24 hours and then challenged with Compound 1 or Compound 2.
[0088] Compound 1 (1 mg / Kg, 3 mg / Kg, 10 mg / Kg, 30 mg / Kg and 100 mg / Kg; PO) was administered and tumors were harvested 2 hours after dosing. Phosphorylation of CHK1(s296) was assessed by immunoblotting and normalized to total ERK expression. Results are expressed as percent control ("POC"). The results are shown in Figure 1.
[0089] Compound 2 (25 mg / kg; PO) was administered, and tumors were harvested at 2 hours, 4 hours, 8 hours and 12 hours after administration. Phosphorylation of CHK1(s296) was assessed by immunoblotting and normalized to total ERK expression. Results are expressed as POC. The results are shown in ...
Embodiment 2
[0091] Female nude mice were subcutaneously inoculated with 5X10 in 1X PBS (100 μL) 6 HT-29 tumor cells. After 20 days, the mice were randomly divided into 3 groups, and the average tumor volume of each group was about 390mm 3 . Female nude mice bearing HT-29 tumors were administered CPT11 (100 mg / kg; IP), and tumors were collected for analysis at 48 hours, 72 hours and 96 hours after administration. Phosphorylation of CHK1 and cdc2 was assessed by immunoblotting and normalized to total ERK expression. Results are expressed as POC. The results are shown in Figures 3 and 4.
Embodiment 3
[0093] Female nude mice were subcutaneously inoculated with 5X10 in 1X PBS (100 μL) 6 HT-29 tumor cells. After 12 days, the mice were randomly divided into 6 groups with an average tumor volume of approximately 250 mm in each group 3 . Sorted animals were administered a single dose of CPT11 (100 mg / kg; IP) for 2 days, followed by Compound 1 (50 mg / kg; PO, BID) for 3 consecutive days either simultaneously or 24 hours after CPT11 administration. Tumor size and animal body weight were measured over the course of the study and the data points are represented in FIG. 5 . Tumor volume was calculated using the following: volume = (width 2 X length) / 2. The results are shown in Figure 5, and the tolerance results are shown in Table 1:
[0094] Table 1
[0095] deal with Maximum weight loss % %mortality rate vehicle 5.5, day 13 0 CPT11 3.9, day 13 0 Compound 1 3.9, day 13 0 Combo at the same time N / A 100 Combo 24 hours delay 18...
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