SAR-020106 is an ATP-competitive, potent, and selective CHK1 inhibitor with an IC50 of 13.3 nM.
SAR-020106 abrogates an etoposide-induced G2 arrest with an IC50 of 55 nmol/L in HT29 cells, and significantly enhances the cell killing of gemcitabine and SN38 by 3.0- to 29-fold in several colon tumor lines in vitro and in a p53-dependent fashion. SAR-020106 inhibits cytotoxic drug-induced autophosphorylation of CHK1 at S296 and blocks the phosphorylation of CDK1 at Y15 in a dose-dependent fashion[1].
SAR-020106 can enhance the antitumor effects of both irinotecan and gemcitabine in vivo with appropriate biomarker changes and minimal toxicity[1]. Although having minimal oral bioavailability in mice (F = 5%), distribution of SAR-020106 following i.p. dosing (40 mg/kg) was sufficient to inhibit CHK1 in the tumors, as shown by inhibition of the irinotecan-induced CHK1 pS296 autophosphorylation. At doses giving inhibition of CHK1 activity in vivo, the selective CHK1 inhibitor SAR-020106 showed no single agent activity in the SW620 xenograft model, and tumors grew at similar rates to the vehicle-treated controls. When dosed (i.p.) in combination with irinotecan, SAR-020106 was observed to potentiate the antitumor activity of the genotoxic drug in the SW620 xenograft model[2].
[1] Walton MI, et al. Mol Cancer Ther. 2010, 9(1):89-100. [2] Reader JC, et al. J Med Chem. 2011, 54(24):8328-42.