NGI‑189 is a selective OST‑A inhibitor. NGI‑189 inhibits the STT3A catalytic subunit of the OST complex and reduces N‑glycosylation of target glycoproteins. NGI‑189 blocks oncogenic and bypass signaling, reduces phosphorylation of EGFR, AKT, p70S6K and S6RP, and induces cell cycle arrest and apoptosis. NGI‑189 markedly suppresses tumor growth and induces tumor regression in non‑small cell lung cancer (NSCLC) xenograft models. NGI‑189 can be used for the research of EGFR‑mutant non‑small cell lung cancer [1].
In Vivo, NGI-189 (10 mg/kg; i.p.; every other day; 8 total doses) elicits significant tumor growth delay in EGFR-mutant NSCLC PDX models as well as in gefitinib-resistant HCC827-GR NSCLC xenograft models[1]. NGI-189 (10 mg/kg; i.p.; every other day) induces significant tumor regression in osimertinib-resistant H1975-OR NSCLC xenografts[1]. NGI-189 (10 mg/kg; i.p.; every other day; 3 total doses) is well tolerated in mice, with no significant toxicity detected in blood work or organ histopathology[1].
In Vitro, NGI-189 (0.09 μM) potently inhibits N-glycosylation in ER-LucT reporter cells with an IC50 of 0.09 μM[1]. NGI-189 (5 μM; 5 days) inhibits proliferation of parental PC9 EGFR mutant NSCLC cells by ~70%, with significant rescue observed in PC9-CD8-EGFR-CL cells that express N-glycosylation-independent EGFR[1]. NGI-189 (0-25 μM; 24 h) preferentially inhibits the OST-A complex in HEK293 wild-type, STT3A KO, and STT3B KO cells, reducing N-glycosylation of EGFR and Halo3N in a dose-dependent manner, with complete inhibition of OST-A-dependent glycosylation achievable only in STT3B KO cells[1]. NGI-189 (10 μM; 24 h) reduces N-glycosylation of bypass PTK7, MET and inhibits downstream STAT3 signaling in Osimertinib -resistant H1975-OR and Gefitinib -resistant HCC827-GR NSCLC cells[1]. NGI‑189 (5 μM) reduces clonogenic survival of parental PC9 EGFR‑mutant NSCLC cells and shows significant rescue in PC9‑CD8‑EGFR‑CL cells expressing N‑glycosylation‑independent EGFR; it also significantly decreases clonogenic survival of H3255, HCC‑4006, and HCC‑2935 EGFR‑mutant NSCLC cells[1]. NGI-189 (5 μM; 24 h) inhibits EGFR and downstream AKT/p70S6K/S6RP signaling, and induces pro-apoptotic Bim protein expression in H3255, HCC-4006, and HCC-2935 EGFR mutant NSCLC cells[1]. NGI-189 (5 μM; 24 h) induces G1 phase cell cycle arrest in PC9 EGFR-mutant NSCLC cells, and triggers G1 arrest accompanied by marked cell death (sub-G1 population) in H3255 and HCC-2935 EGFR-mutant NSCLC cells[1].
References:
[1]. Baro M, et al. Redundancy of the OST catalytic subunit facilitates therapeutic targeting of N-glycosylation. Cell Chem Biol. 2025;32(6):839-853.e6.
In Vivo, NGI-189 (10 mg/kg; i.p.; every other day; 8 total doses) elicits significant tumor growth delay in EGFR-mutant NSCLC PDX models as well as in gefitinib-resistant HCC827-GR NSCLC xenograft models[1]. NGI-189 (10 mg/kg; i.p.; every other day) induces significant tumor regression in osimertinib-resistant H1975-OR NSCLC xenografts[1]. NGI-189 (10 mg/kg; i.p.; every other day; 3 total doses) is well tolerated in mice, with no significant toxicity detected in blood work or organ histopathology[1].
In Vitro, NGI-189 (0.09 μM) potently inhibits N-glycosylation in ER-LucT reporter cells with an IC50 of 0.09 μM[1]. NGI-189 (5 μM; 5 days) inhibits proliferation of parental PC9 EGFR mutant NSCLC cells by ~70%, with significant rescue observed in PC9-CD8-EGFR-CL cells that express N-glycosylation-independent EGFR[1]. NGI-189 (0-25 μM; 24 h) preferentially inhibits the OST-A complex in HEK293 wild-type, STT3A KO, and STT3B KO cells, reducing N-glycosylation of EGFR and Halo3N in a dose-dependent manner, with complete inhibition of OST-A-dependent glycosylation achievable only in STT3B KO cells[1]. NGI-189 (10 μM; 24 h) reduces N-glycosylation of bypass PTK7, MET and inhibits downstream STAT3 signaling in Osimertinib -resistant H1975-OR and Gefitinib -resistant HCC827-GR NSCLC cells[1]. NGI‑189 (5 μM) reduces clonogenic survival of parental PC9 EGFR‑mutant NSCLC cells and shows significant rescue in PC9‑CD8‑EGFR‑CL cells expressing N‑glycosylation‑independent EGFR; it also significantly decreases clonogenic survival of H3255, HCC‑4006, and HCC‑2935 EGFR‑mutant NSCLC cells[1]. NGI-189 (5 μM; 24 h) inhibits EGFR and downstream AKT/p70S6K/S6RP signaling, and induces pro-apoptotic Bim protein expression in H3255, HCC-4006, and HCC-2935 EGFR mutant NSCLC cells[1]. NGI-189 (5 μM; 24 h) induces G1 phase cell cycle arrest in PC9 EGFR-mutant NSCLC cells, and triggers G1 arrest accompanied by marked cell death (sub-G1 population) in H3255 and HCC-2935 EGFR-mutant NSCLC cells[1].
References:
[1]. Baro M, et al. Redundancy of the OST catalytic subunit facilitates therapeutic targeting of N-glycosylation. Cell Chem Biol. 2025;32(6):839-853.e6.