GDC-0425

GDC-0425 (RG-7602) is an orally available, highly selective small molecule ChK1 inhibitor. GDC-0425 can be used for the research of various malignancies[1][2].

Research Areas >> Cancer

Signaling Pathways >> Cell Cycle/DNA Damage >> Checkpoint Kinase (Chk)

Chk1

MEK inhibition either by pharmacologic inhibitors or RNAi-mediated gene silencing significantly protected cells from reduced viability upon GDC-0425 treatment[3]. GDC-0425 (3 μM; 24 hours) treatment results the hyperphosphorylation of Chk1[3]. Cell Viability Assay[3] Cell Line: Chk1-positive breast cancer cell lines Concentration: 0.001, 0.01, 0.1, 1, 10 mM Incubation Time: 72 hours Result: Reduced cell proliferation. Cell Viability Assay[3] Cell Line: U-2 OS cells Concentration: 3 μM Incubation Time: 24 hours Result: Led to hyperphosphorylation of Chk1.

GDC-0425 exhibits partial suppression of tumor growth. The Gemcitabine/GDC-0425 combination results in significant tumor regression in all tested models[3]. Animal Model: NCr nude mice bearing xenografts of both osteosarcoma and triple-negative breast cancer models (143B PML BK TK, HCC1806, and HCC70 cell lines)[3] Dosage: For the 4-arm study, mice were treated with vehicle, Gemcitabine 120 mg/kg, GDC-0425 75 mg/kg alone, or Gemcitabine and GDC-0425 combination for 15 days. For 6-arm studies of HCC1806 and HCC70 models, mice were treated with vehicle, Gemcitabine 120 mg/kg, GDC-0425 50 mg/kg, GDC-0425 75 mg/kg alone, or Gemcitabine and GDC-0425 combination. Administration: Orally administrated at 24, 48, and 72 hours after gemcitabine administration by intraperitoneal injection. Result: Exhibited partial suppression of tumor growth upon treatment with either Gemcitabine or GDC-0425 alone. Notably, the Gemcitabine/GDC-0425 combination resulted in significant tumor regression in all tested models.

[1]. Xiao Ding, et al. A supported liquid extraction LC-MS/MS method for determination of concentrations of GDC-0425, a small molecule Checkpoint kinase 1 inhibitor, in human plasma. Biomed Chromatogr. 2016 Dec;30(12):1984-1991.

[2]. Jeffrey R Infante, et al. Phase I Study of GDC-0425, a Checkpoint Kinase 1 Inhibitor, in Combination with Gemcitabine in Patients with Refractory Solid Tumors. Clin Cancer Res. 2017 May 15;23(10):2423-2432.

[3]. Ho-June Lee, et al. Ras-MEK Signaling Mediates a Critical Chk1-Dependent DNA Damage Response in Cancer Cells. Mol Cancer Ther. 2017 Apr;16(4):694-704.