hSMG-1 inhibitor 11j, a pyrimidine derivative, is a potent and selective inhibitor of hSMG-1, with an IC50 value of 0.11nM [1]. hSMG-1 inhibitor 11j can inhibit the phosphorylation of UPF1 by SMG1, increase the abundance of sTARDBP, and participate in the regulation of nonsense-mediated RNA decay (NMD) [2]. hSMG-1 inhibitor 11j has been widely used in the regulation of exon junction complex (EJC) and in non-dependent and EJC-enhanced reporter gene systems[3].
In vitro, hSMG-1 inhibitor 11j treatment (0.3μM) for 2h significantly reduced the phosphorylation of UPF1 at the T28 site and enhanced the expression levels of co-stimulatory molecules Cd40 and Cd80 in bone marrow-derived dendritic cells (BMDCs) [4]. Treatment of fibroblasts with hSMG-1 inhibitor 11j (0.5μM) for 20 hours resulted in a significant increase in LNPK RNA levels[5]. Treatment with 9.6μM hSMG-1 inhibitor 11j for 72 hours can induce apoptosis in A549 cells, reduce the viability of tumor cells, and enhance radio-sensitivity[6].
In vivo, injecting a single dose of 6µg of hSMG-1 inhibitor 11j (dissolved in 25µl of physiological saline) into the hind paw of mice for three hours can induce mechanical pain in the mice without causing thermal hyperalgesia[7].
References:
[1] Gopalsamy A, Bennett E M, Shi M, et al. Identification of pyrimidine derivatives as hSMG-1 inhibitors[J]. Bioorganic & medicinal chemistry letters, 2012, 22(21): 6636-6641.
[2] Dykstra M M, Weskamp K, Gómez N B, et al. TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms[J]. Cell reports, 2025, 44(1).
[3] Kolakada D, Campbell A E, Galvis L B, et al. A system of reporters for comparative investigation of EJC-independent and EJC-enhanced nonsense-mediated mRNA decay[J]. Nucleic Acids Research, 2024, 52(6): e34-e34.
[4] Mino T, Iwai N, Endo M, et al. Translation-dependent unwinding of stem–loops by UPF1 licenses Regnase-1 to degrade inflammatory mRNAs[J]. Nucleic acids research, 2019, 47(16): 8838-8859.
[5] Doss R M, Wirth S A, Pitsch J W, et al. Exon-skipping due to bi-allelic splice site mutations in the neurodevelopmental disease gene LNPK[J]. Human Genetics and Genomics Advances, 2026, 7(1).
[6] Gudikote J P, Cascone T, Poteete A, et al. Inhibition of nonsense-mediated decay rescues p53β/γ isoform expression and activates the p53 pathway in MDM2-overexpressing and select p53-mutant cancers[J]. Journal of Biological Chemistry, 2021, 297(5): 101163.
[7] De La Peña J B, Chase R, Kunder N, et al. Inhibition of nonsense-mediated decay induces nociceptive sensitization through activation of the integrated stress response[J]. Journal of Neuroscience, 2023, 43(16): 2921-2933.
hSMG-1 inhibitor 11j是一种嘧啶衍生物，是一种强效且选择性的hSMG-1抑制剂，IC50值为0.11nM[1]。hSMG-1 inhibitor 11j可抑制SMG1介导的UPF1磷酸化，增加sTARDBP的丰度，并参与无义介导的RNA衰变(NMD)的调控[2]。hSMG-1 inhibitor 11j已被广泛用于外显子连接复合体的调控以及非依赖性和EJC增强的报告基因系统中[3]。
在体外，使用0.3μM的hSMG-1 inhibitor 11j处理骨髓来源的树突状细胞(BMDCs) 2小时，显著降低了UPF1在T28位点的磷酸化，并增强了共刺激分子Cd40和Cd80的表达水平[4]。用0.5μM的hSMG-1 inhibitor 11j处理成纤维细胞20小时，导致LNPK的RNA水平显著增加[5]。用9.6μM的hSMG-1 inhibitor 11j处理A549细胞72小时，可诱导细胞凋亡，降低肿瘤细胞活力，并增强放射敏感性[6]。
在体内，向小鼠后爪单次注射6μg的hSMG-1 inhibitor 11j（溶于25μl生理盐水中）3小时，可诱发小鼠机械性疼痛，而不引起热痛觉过敏[7]。