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.
UCPH-101是一种兴奋性氨基酸转运蛋白亚型1（EAAT1）抑制剂，IC50值为0.66μM[1]。UCPH-101是一种慢结合、非竞争性的EAAT1抑制剂，它阻断转运循环中的转位过程，而非其他部分反应[2]。UCPH-101能够阻断右美托咪定（dexmedetomidine）和胍法辛（guanfacine）的神经保护作用[3]。UCPH-101能够通过诱导细胞内谷氨酸积累而导致胶质母细胞瘤细胞死亡，并在胶质瘤小鼠模型中显著提高了生存[4]。
在体外，UCPH-101（20µM）处理小鼠MA9-1细胞和人U937细胞6-24h，均显著升高了两种细胞的凋亡水平，导致了G1期细胞减少、S期及G2/M期细胞相应增加[5]。UCPH-101（10µM）处理GL261-NS细胞、GBM-NS细胞以及星形胶质细胞，显著升高了GL261-NS和GBM-NS细胞的凋亡水平，但不影响星形胶质细胞的凋亡水平[6]。
在体内，UCPH-101（10nmol/μL）通过颅内注射给药治疗胶质瘤细胞异种移植小鼠，显著提高了小鼠存活率，显著破坏了脑胶质瘤的组织结构，显著下调了肿瘤组织中谷氨酸-天冬氨酸转运体（GLAST）的表达水平，显著升高了裂解型Caspase-3的表达水平[6]。