GDC-0425 (RG-7602) is an orally administered, selective small molecule inhibitor of checkpoint kinase 1 (ChK1), used in research on various malignancies [1] [2].

Inhibition of MEK through pharmacologic inhibitors or RNAi-mediated gene silencing significantly enhanced cellular resistance to reduced viability when treated with GDC-0425 [3]. Administration of GDC-0425 (3 μM; 24 hours) induced hyperphosphorylation of Chk1 in cells [3]. In Chk1-positive breast cancer cell lines, exposure to varying concentrations of GDC-0425 (0.001, 0.01, 0.1, 1, 10 mM) over 72 hours demonstrated a decrease in cell proliferation. Similarly, U-2 OS cells treated with 3 μM of GDC-0425 for 24 hours experienced Chk1 hyperphosphorylation, indicating altered checkpoint kinase signalling [3].

GDC-0425 has been shown to partially suppress tumor growth when used alone. However, when combined with Gemcitabine, it significantly regresses tumors across all tested models, including NCr nude mice xenografts of osteosarcoma and triple-negative breast cancer (143B PML BK TK, HCC1806, and HCC70 cell lines). In the 4-arm study, mice received treatments of a vehicle, Gemcitabine at 120 mg/kg, GDC-0425 at 75 mg/kg alone, or a combination of Gemcitabine and GDC-0425 for 15 days. The 6-arm studies focused on HCC1806 and HCC70 models included an additional GDC-0425 dosage of 50 mg/kg. Administration was orally delivered at 24, 48, and 72 hours post-Gemcitabine injection intraperitoneally. The combination therapy not only exhibited partial suppression of tumor growth with either Gemcitabine or GDC-0425 alone but also led to significant tumor regression in all models tested.