OSMI-1

OSMI-1 is an O-GlcNAc transferase (OGT) small molecule inhibitor that does not significantly affect other glycosyltransferases ^[1]. OSMI-1 inhibited full length human OGT (ncOGT) with an IC50 value of 2.7 µM ^[2].

OSMI-1 ranging from 10 to 100 µM treated inhibited global O-GlcNAcylation in Chinese hamster ovary (CHO) cells with the maximal effect being achieved at 50 µM ^[2]. 50 µM OSMI-1 treated CHO cells decreased viability by about 50% after 24 h ^[2]. OSMI-1 (40 µM) decreased total-O-GlcNAc by 30% in both TamS and TamR cells lines ^[1]. TamR cells were significantly more sensitive to OSMI-1 than the parental TamS cells, with OSMI-1-EC50 value of ~15 µM in TamR and ~ 40 µM in TamS by activity for proliferation assay ^[1]. OSMI-1 (40 µM, 24 h) increased expression of OGT and DDIT3 in both TamS and TamR cells while ERα is downregulated ^[1]. The levels of intracellular and secreted HBsAg, but not HBeAg, in the supernatants increased in primary human hepatocytes (PHHs) and HepG2.2.15 cells after OSMI-1 treatment ^[3].

OSMI-1 reduced osteoclast differentiation in vivo by disrupting the translocation of NF-κB p65 and nuclear factor of activated T cells c1 (NFATc1) into the nucleus by controlling their PTM O-GlcNAcylation. OSMI-1 treatment effectively inhibited lipopolysaccharide (LPS)-induced formation of TRAP-positive osteoclasts in the cavarial surface compared to the mice injected with the vehicle, while OSMI-1 significantly reduced the number of TRAP-specific mature osteoclasts in the calvarial surfaces and sections ^[4]. The tumor size in mice treated with TRAIL or OSMI-1 alone was slightly reduced compared with the control group but was significantly reduced (5-fold) in the TRAIL and OSMI-1 combination group on HCT116 Xenograft in Nude Mice. Compared with vehicle-treated xenograft mice, the levels of ER stress-related proteins, such as IRE1α, PERK, p-JNK, CHOP and DR5, were increased when either TRAIL or OSMI-1 was administered alone, whereas these effects were even greater for the combination treatment ^[5].

References:
[1]. Barkovskaya A, Seip K, Prasmickaite L, et al. Inhibition of O-GlcNAc transferase activates tumor-suppressor gene expression in tamoxifen-resistant breast cancer cells[J]. Scientific reports, 2020, 10(1): 1-10.
[2]. Ortiz-Meoz R F, Jiang J, Lazarus M B, et al. A small molecule that inhibits OGT activity in cells[J]. ACS chemical biology, 2015, 10(6): 1392-1397.
[3]. Wang X, Lin Y, Liu S, et al. O-GlcNAcylation modulates HBV replication through regulating cellular autophagy at multiple levels[J]. The FASEB Journal, 2020, 34(11): 14473-14489.
[4].Kim M J, Kim H S, Lee S, et al. Hexosamine Biosynthetic Pathway-Derived O-GlcNAcylation Is Critical for RANKL-Mediated Osteoclast Differentiation[J]. International Journal of Molecular Sciences, 2021, 22(16): 8888.
[5]. Lee S J, Lee D E, Choi S Y, et al. OSMI-1 enhances TRAIL-induced apoptosis through ER stress and NF-κB signaling in colon cancer cells[J]. International journal of molecular sciences, 2021, 22(20): 11073.