Background:

XL413 is a potent, selective and ATP competitive inhibitor of Cdc7, with an IC50 of 3.4 nM, and also shows potent effect with IC50s of 215, 42 nM on CK2, PIM1, respectively, and an EC50 of 118 nM on pMCM.

XL413 inhibits the cell proliferation (IC50 = 2685 nM), decreases cell viability (IC50 = 2142 nM) and elicits the caspase 3/7 activity (EC50 = 2288 nM) in Colo-205 cells. XL413 also significantly inhibits the anchorage-independent growth of colo-205 in soft agar (IC50 = 715 nM)[1]. XL413 shows cytotoxic effects on tumors, with IC50 of 22.9 μM in HCC1954 cells and 1.1 μM in Colo-205 cells. XL413 induces apoptosis in the Colo-205 cells, but not in HCC1954 cells. XL413 is effective DDK inhibitors in vitro, with IC50 of 22.7 nM. XL413 is defective in inhibiting DDK-dependent Mcm2 phosphorylation in HCC1954 cells but is effective in Colo-205 cells[2].

XL413 (100 mg/kg, p.o.) shows excellent plasma exposures in mice and possesses good PK properties. XL413 (10, 30, or 100 mg/kg, p.o.) is well tolerated at all the doses, with no significant body weight loss[1].

参考文献:
[1]. Koltun ES, et al. Discovery of XL413, a potent and selective CDC7 inhibitor. Bioorg Med Chem Lett. 2012 Jun 1;22(11):3727-31.
[2]. Sasi NK, et al. The potent Cdc7-Dbf4 (DDK) kinase inhibitor XL413 has limited activity in many cancer cell lines and discovery of potential new DDK inhibitor scaffolds. PLoS One. 2014 Nov 20;9(11):e113300.