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.
OSMI-1是一种O-GlcNAc转移酶（OGT）小分子抑制剂，不会显著影响其他糖基转移酶[1]。OSMI-1抑制全长人OGT（ncOGT），IC50值为2.7µM[2]。
10至100µM的OSMI-1处理抑制了中国仓鼠卵巢（CHO）细胞的整体O-GlcNAcylation，在50µM时达到最大效果[2]。50µM OSMI-1处理的CHO细胞在24小时后活力降低约50%[2]。OSMI-1（40µM）使TamS和TamR细胞系中的总-O-GlcNAc降低了30%[1]。TamR细胞对OSMI-1的敏感性明显高于亲代TamS细胞，通过增殖活性测定，TamR中OSMI-1-EC50值约为15µM，TamS中OSMI-1-EC50值为约40µM[1]。OSMI-1（40µM，24小时）增加了TamS和TamR细胞中OGT和DDIT3的表达，而ERα下调[1]。OSMI-1处理后，原代人肝细胞（PHHs）和HepG2.2.15细胞上清液中细胞内和分泌的HBsAg水平增加，但HBeAg水平没有增加[3]。
OSMI-1通过控制其PTM-O-GlcNAcylation，破坏NF-κB p65和活化T细胞核因子c1（NFATc1）向细胞核的易位，从而在体内减少破骨细胞分化。与注射载体的小鼠相比，OSMI-1治疗有效抑制了脂多糖（LPS）诱导的颅骨表面TRAP阳性破骨细胞的形成，而OSMI-1显著减少了颅骨表面和切片中TRAP特异性成熟破骨细胞数量[4]。与对照组相比，单独用TRAIL或OSMI-1处理的小鼠中的肿瘤大小略有减小，但在裸小鼠中的HCT116异种移植物上，TRAIL和OSMI-1组合组中的肿瘤尺寸显著减小（5倍）。与载体处理的异种移植物小鼠相比，当单独施用TRAIL或OSMI-1时，ER应激相关蛋白（如IRE1α、PERK、p-JNK、CHOP和DR5）的水平增加，而联合治疗的这些作用甚至更大[5]。