NGI-1 (ML414) is an effective oligosaccharyl transferase (OST) inhibitor [1]. NGI-1 selectively inhibits the STT3A and STT3B subunits in the oligosaccharyl transferase (OST) complex, thereby blocking the N-linked glycosylation process of proteins [2-3]. NGI-1 is often used to study the regulation of glycosylation-dependent proteins such as EGFR in tumor cells and has certain anti-tumor potential [4].
In PC9 cells, NGI-1 (10μM; 48h) reduced the proliferation of both parental and T790M-expressing PC9 cell lines by approximately 90% [5]. In HEK293 cells, NGI-1 (5μM; 60min) treatment results in cell type-dependent dysfunction of HSV-1 [2]. In Caco2 cells, NGI-1 (1μM, 5μM; 3d) has a significant inhibitory effect on SARS-CoV-2 [6]. In SKMG3 cells, NGI-1 (10μM; 48h) disrupts RTK signaling in glioblastoma cells [7].
In oral squamous cell carcinoma xenograft model, combined inhibition of EREG glycosylation by targeting NGI-1 (10mg/kg; ip; 14d) significantly enhanced the efficacy of anti-PDL1 inhibitors in vivo [8]. In lung adenocarcinoma xenograft model, the tumor volume and wet weight of NGI-1 (20mg/kg; ip; 24d) treated mice were significantly smaller than those of the DMSO control group at the end point [9]. In CD24-WT nude mice, NGI-1 (20mg/kg; ip; 24d) treatment significantly inhibited tumor growth [10].
References:
[1]. Rinis N, Golden JE, Marceau CD, et al. Editing N-glycan site occupancy with small-molecule oligosaccharyltransferase inhibitors. Cell chemical biology. 2018 Oct 18; 25(10): 1231-1241.
[2]. Lu H, Cherepanova NA, Gilmore R, et al. Targeting STT3A-oligosaccharyltransferase with NGI-1 causes herpes simplex virus 1 dysfunction. The FASEB Journal. 2019 Feb 27;33(6):6801.
[3]. Harada Y, Ohkawa Y, Kizuka Y, et al. Oligosaccharyltransferase: a gatekeeper of health and tumor progression. International journal of molecular sciences. 2019 Dec 2; 20(23): 6074.
[4]. Cao Y, Yi W, Zhu Q. Glycosylation in the tumor immune response: the bitter side of sweetness: Glycosylation in the tumor immune response. Acta Biochimica et Biophysica Sinica. 2024 Jun 28; 56(8): 1184.
[5]. Lopez Sambrooks C, Baro M, Quijano A, et al. Oligosaccharyltransferase inhibition overcomes therapeutic resistance to EGFR tyrosine kinase inhibitors. Cancer research. 2018 Sep 1; 78(17): 5094-5106.
[6]. Huang YJ, Zhao H, Huang X, et al. Identification of oligosaccharyltransferase as a host target for inhibition of SARS-CoV-2 and its variants. Cell Discovery. 2021 Nov 30; 7(1): 116.
[7]. Baro M, Lopez Sambrooks C, Quijano A, et al. Oligosaccharyltransferase inhibition reduces receptor tyrosine kinase activation and enhances glioma radiosensitivity. Clinical Cancer Research. 2019 Jan 15; 25(2): 784-795.
[8]. Xu S, Wang H, Zhu Y, et al. Stabilization of EREG via STT3B-mediated N-glycosylation is critical for PDL1 upregulation and immune evasion in head and neck squamous cell carcinoma. International Journal of Oral Science. 2024 Jul 1; 16(1): 47.
[9]. Cheng J, Xia L, Hao X, et al, Tavolari S. Targeting STT3A produces an anti-tumor effect in lung adenocarcinoma by blocking the MAPK and PI3K/AKT signaling pathway. Translational Lung Cancer Research. 2022 Jun; 11(6): 1089.
[10]. Wang J, Zhang HM, Zhu GH, et al. STT3-mediated aberrant N-glycosylation of CD24 inhibits paclitaxel sensitivity in triple-negative breast cancer. Acta Pharmacologica Sinica. 2025 Apr; 46(4): 1097-1110.