Glutamate dehydrogenase 1 (GLUD1) is a key enzyme in the breakdown of glutamine, which can convert glutamic acid into alpha ketoglutarate and enter the TCA cycle. Specifically, GLUD is activated by the direct binding of the essential amino acid leucine, thereby stimulating glutamic acid deamination and producing alpha KG. Besides, GLUD has two different isoenzymes, GLUD1 and GLUD2, both of which are upregulated in human cancer, allowing cancer cells to utilize this pathway for growth and proliferation. Knockdown of GDH1 significantly reduced the cell proliferation, colony formation, and tumorigenesis ability of glioblastoma cells. In addition, GDH1 mediated glutamine breakdown is involved in EGF promoted cell proliferation. Moreover, phosphorylated ELK1 is enriched on the promoter of GDH1, thereby activating the transcription of GDH1 and promoting glutamine metabolism. Here, we will introduce a potent GDH1/GLUD1 inhibitor for kinds of cancers research, R162.

R162 is a Potent GDH1/GLUD1 Inhibitor for Kinds of Cancers Research.

First of all, Inhibition of GDH1 activity by R162 treatment results in decreased intracellular fumarate levels. And it causes attenuated GPx activity, increased ROS levels, and reduced cell proliferation in H1299 and MDA-MB231 cells. Meanwhile, this can be significantly rescued by methyl-α-KG treatment as well as by antioxidant NAC. Nonetheless, R162 inhibits cell proliferation and tumor growth potential of human cancer cells.

In the second place, R162 does not result in a significant histopathological change between the vehicle-treated and R162-treated groups. Particularly, R162 does not alter complete blood counts, or hematopoietic properties in xenograft tumor mouse models.

Last but not the least, R162 results in significantly decreased tumor growth and masses in mice compared with control mice. Additionally, R162 effectively inhibits GDH1 activity in resected tumors from xenograft nude mice.

All in all, R162 is a potent GDH1/GLUD1 inhibitor for kinds of cancers research.

References:

[1] Jin L, et al. Cancer Cell. 2015 Feb 9;27(2):257-70.