Cancer cells always exhibit abnormal energy metabolism. Abnormal energy metabolism often leads to an increase in glucose uptake and lactic acid fermentation.
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an important catalyzing enzyme for glycolysis. GAPDH catalyzes key steps at the center of the glycolysis process. And this process is the convergence point for feeder pathways or alternative ATP-generating pathways. Whatmore, the first step in NADH production is the hydrolyzation of glyceraldehyde-3-phosphate. GAPDH is overexpressed in many cancers, Overexpression of GAPDH aggravates cancer progression and promotes cell proliferation.

In this article, we will introduce a potent GAPDH inhibitor, DC-5163 has an IC50 of 176.3 nM and a Kd of 3.192 μM.

In MDA-MB-231 cells, DC-5163 treatment induces the apoptosis of the cells. It also significantly reduces glucose uptake, lactate production, and 18F-FDG uptake rate when compares to control.
Additionally, DC-5163 treatment at 25 μM inhibits GAPDH activity in BT-549 cells, MCF7 cells, HCT116 cells, MDA-MB-231 cells, and A549 cells after 48 hours. This compound inhibits MDA-MB-231 cell proliferation with an IC50 of 99.22 μM at 48 hours.

Normal cells MCF-10A are tolerant of DC-5163. At the same time, it inhibits GAPDH activity at both the isolated protein and intracellular levels. All the above cells derive from epithelial tissue, As a result, DC-5163 may reduce GAPDH activity in epithelial tissue-derived tumors.

There manifest sufficient reasons that DC-5163 may play an important role in the targeted therapy of cancer. GAPDH is an effective target for tumor therapy. Moreover, DC-5163, as a potent GAPDH inhibitor, providing a basis for further drug development.
In conclusion, DC-5163 inhibits GAPDH enzyme activity in vitro, partially blocks the glycolytic pathway. Besides, it inhibits cancer cell proliferation and induces cell apoptosis. Meanwhile, normal cells are highly tolerant of this inhibitor.
All in all, Compound DC-5163 is a promising compound for further study of the function of GAPDH. It facilitates the research and development of GAPDH-targeting agents and manifesting a bright future for application.


Li T, et al. Bioorg Chem. 2020 Mar;96:103620.