OSMI-2 (Compound 1b; 20-50 μM; 4-24 hours; HCT116 cells) treatment reduces O-GlcNAc levels at short treatment times (<8h). However, O-GlcNAc levels begins to recover at longer treatment times with OSMI-2[1].A decrease in HCF-1 cleavage products and the appearance of uncleaved HCF-1 in cells treated with OSMI-2 (Compound 1b) is observed. Because OGT knockdown is known to decrease cell proliferation, the effects of OSMI-2 on cell growth in culture over 96h is also monitored. Although there is no evidence of apoptosis, the reduced growth of cells over time is observed, consistent with the knockdown results[1].
A time course performed with 20 μM OSMI-2 (Compound 1b) shows reciprocal changes in the abundance of OGT and OGA, with a particularly large increase in OGT; this may explain the recovery in O-GlcNAc levels with OSMI-2. At 24h where O-GlcNAc levels fully recovered[1].
References:
[1]. Martin SES, et al. Structure-Based Evolution of Low Nanomolar O-GlcNAc Transferase Inhibitors. J Am Chem Soc. 2018 Oct 24;140(42):13542-13545.