A Chk1 inhibitor
GDC-0575 is an inhibitor of checkpoint kinase 1 (Chk1; IC50 = 1.2 nM).1 It is greater than 30-fold selective for Chk1 over a panel of more than 450 wild-type and mutant kinases. GDC-0575 (500 nM) enhances apoptosis induced by cytarabine in HL-60, KG-1, U937, and ML-1 human acute myeloid leukemia (AML) cells. It nearly completely eliminates tumor burden in AML patient-derived xenograft (PDX) mouse models when administered at a dose of 7.5 mg/kg in combination with cytarabine.
1.Di Tullio, A., Rouault-Pierre, K., Abarrategi, A., et al.The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemiaNat. Commun.8(1)1679(2017)
Cell experiment: | AML cell lines are seeded at 1×104 cells/well in 96-well plates in triplicate, and subjected to different treatment conditions. After 24 h of incubation with GDC-0575, cell proliferation is measured with the XTT Cell Proliferation Kit II[3]. |
Animal experiment: | Mice[1]Female nude BALB/c mice are injected with 2-3×106 melanoma cells in Matrigel by subcutaneous injection on the hind flank. Once tumors reach approximately 100 mm3, mice are treated with GDC-0575 (25 mg/kg, 50 mg/kg) or vehicle (0.5% w/v methylcellulose and 0.2%v/v Tween 80) by oral gavage for 3 cycles where one cycle is three consecutive days of treatment followed by four rest days. Tumor size is measured three times per week using calipers. Mice are sacrificed at up to 6 weeks after terminating the treatment or when tumor size measured >1 cm3[1]. |
参考文献: [1]. Oo ZY, et al. Endogenous Replication Stress Marks Melanomas Sensitive to CHEK1 Inhibitors In Vivo. Clin Cancer Res. 2018 Mar 13. doi: 10.1158/1078-0432.CCR-17-2701. | |
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