NMDI14 is potent inhibitor of nonsense mediated RNA decay (NMD)[1]. NMDI14 prevents the formation of the UPF1-SMG7 (or UPF1-SMG5) heterodimers, suppresses NMD and stabilizes W1282X mRNA [2]. NMDI14 has been widely used as a model compound to develop a series of derivatives and serve as anti-mesothelioma agents in vitro[3].
In vitro, NMDI14 treatment at 50μM for 6 hours significantly increased the expression level of p53 mRNA in U2OS cells, without affecting cell viability[4]. After treating primary nasal epithelial cells of W1282X heterozygous carriers with 5μM NMDI14 for 12 hours, the level of W1282X transcripts was significantly increased[5]. Treatment with 50 μM NMDI14 for 72 hours can prevent the upregulation of ABCC1 and ABCC2 mRNA mediated by human papilloma virus (HPV) 18 E6/E7 proteins in HNO206 cells[6]. 0.1μM of NMDI14 and CC-90009 (7.5nM) treatment for 2 days significantly promoted the increase in the expression of type XVII collagen in JEB-C17 keratinocytes without affecting cell viability[7].
In, vivo, NMDI14 treatment via intracerebroventricular injection (2μL; 674 μM) three times within 24h in a mouse model of status epilepticus significantly reduced the spontaneous epileptic seizures that occurred following the persistent state of epilepsy[8].
References:
[1] Evtushenko N, Beilin A, Novikov A, et al. 163 Nonsense-mediated mRNA decay inhibitors perspectives for recessive dystrophic epidermolysis bullosa treatment[J]. Journal of Investigative Dermatology, 2021, 141(10): S176.
[2] Ensinck M M, Carlon M S. One size does not fit all: the past, present and future of cystic fibrosis causal therapies[J]. Cells, 2022, 11(12): 1868.
[3] Nguyen H N, Suzuki K, Kimura Y, et al. Synthesis and biological evaluation of NMDI14 derivatives as anti-mesothelioma agents[J]. Heterocycles, 2020, 100(2): 253-266.
[4] Martin L, Grigoryan A, Wang D, et al. Identification and characterization of small molecules that inhibit nonsense-mediated RNA decay and suppress nonsense p53 mutations[J]. Cancer research, 2014, 74(11): 3104-3113.
[5] Aksit M A, Bowling A D, Evans T A, et al. Decreased mRNA and protein stability of W1282X limits response to modulator therapy[J]. Journal of Cystic Fibrosis, 2019, 18(5): 606-613.
[6] Rigalli J P, Reichel M, Tocchetti G N, et al. Human papilloma virus (HPV) 18 proteins E6 and E7 up-regulate ABC transporters in oropharyngeal carcinoma. Involvement of the nonsense-mediated decay (NMD) pathway[J]. Cancer letters, 2018, 428: 69-76.
[7] Sayar S B, Has C. Strategy for the optimization of read-through therapy for junctional epidermolysis bullosa with COL17A1 nonsense mutation[J]. Journal of Investigative Dermatology, 2024, 144(10): 2221-2229. e1.
[8] Mooney C M, Jimenez-Mateos E M, Engel T, et al. RNA sequencing of synaptic and cytoplasmic Upf1-bound transcripts supports contribution of nonsense-mediated decay to epileptogenesis[J]. Scientific reports, 2017, 7(1): 41517.