UCPH-101 is an inhibitor of Excitatory Amino Acid Transporter 1 (EAAT1), with an IC50 value of 0.66μM[1]. UCPH-101 acts as a slow-binding, non-competitive EAAT1 inhibitor; it blocks the translocation step within the transport cycle rather than other partial reactions[2]. UCPH-101 is capable of blocking the neuroprotective effects of dexmedetomidine and guanfacine[3]. UCPH-101 induces glioblastoma cell death by promoting the intracellular accumulation of glutamate and has been shown to significantly improve survival in mouse models of glioma[4].
In vitro, treatment of murine MA9-1 cells and human U937 cells with UCPH-101 (20μM) for 6-24 hours significantly increased apoptotic levels in both cell lines, resulting in a decrease in cells in the G1 phase and a corresponding increase in cells in the S and G2/M phases[5]. Treatment of GL261-NS cells, GBM-NS cells, and astrocytes with UCPH-101 (10μM) significantly elevated apoptotic levels in the GL261-NS and GBM-NS cells, while having no effect on the apoptotic levels of the astrocytes[6].
In vivo, intracranial administration of UCPH-101 (10nmol/μL) to mice bearing glioma xenografts significantly improved survival rates. Furthermore, the treatment significantly disrupted the tissue architecture of the brain gliomas, significantly downregulated the expression levels of the glutamate-aspartate transporter (GLAST) within the tumor tissue, and significantly upregulated the expression levels of cleaved Caspase-3[6].
References:
[1] Huynh T H V, Abrahamsen B, Madsen K K, et al. Design, synthesis and pharmacological characterization of coumarin-based fluorescent analogs of excitatory amino acid transporter subtype 1 selective inhibitors, UCPH-101 and UCPH-102[J]. Bioorganic & medicinal chemistry, 2012, 20(23): 6831-6839.
[2] Dong Y. Functional Studies of Amino Acid Transporters from the Solute Carrier SLC1 and SLC38 Families[D]. State University of New York at Binghamton, 2024.
[3] Mei B, Xu X, Weng J, et al. Activating astrocytic α2A adrenoceptors in hippocampus reduces glutamate toxicity to attenuate sepsis-associated encephalopathy in mice[J]. Brain, Behavior, and Immunity, 2024, 117: 376-398.
[4] Corbetta C, Di Ianni N, Bruzzone M G, et al. Altered function of the glutamate aspartate transporter GLAST in glioblastoma[J]. bioRxiv, 2018: 287623.
[5] Tirado H A, Balasundaram N, Jacobs J, et al. The EAAT1 aspartate/glutamate transporter is dispensable for acute myeloid leukemia cell growth and response to therapy[J]. Plos one, 2026, 21(2): e0329048.
[6] Corbetta C, Di Ianni N, Bruzzone M G, et al. Altered function of the glutamate–aspartate transporter GLAST, a potential therapeutic target in glioblastoma[J]. International journal of cancer, 2019, 144(10): 2539-2554.