NV914

NV914 is an inhibitor of FTSJ1 (tryptophan tRNA-specific 2'-O-methyltransferase) that inhibits the methyltransferase activity of FTSJ1, induces translational readthrough of premature termination codons, and enables genes carrying nonsense mutations to synthesize full-length proteins. NV914 belongs to translational readthrough-inducing compounds (TRIDs). NV914 exhibits translational readthrough activity against nonsense mutations in in vitro systems, does not induce readthrough of natural termination codons, and restores CFTR protein expression. NV914 shows favorable acute oral tolerance in mice, with low health risks and good safety profiles. NV914 is applicable to research related to cystic fibrosis and Shwachman-Diamond syndrome ^{[1] [2] [3]}.

In Vivo, NV914 (2000 mg/kg; p.o.; single dose) is well-tolerated in healthy C57BL/6 mice, with temporary toxicity signs and no significant organ damage, classifying it as GHS category 5 (low health risk)^[2].

In Vitro, NV914 (3-48 μM; 24 h) does not induce NTC readthrough in HCT116 cells, as no higher molecular weight p53 bands are detected after treatment plus Doxorubicin^[1]. NV914 (3-48 μM; 24 h) does not alter p53 nuclear localization in HCT116 cells after treatment plus Doxorubicin^[1]. NV914 (3-48 μM; 24 h) does not impair p53 functionality (as measured by p21 mRNA expression) in HCT116 cells after treatment plus Doxorubicin^[1]. NV914 (12-100 μM; 24 or 72 h) does not induce NTC readthrough in 16HBE cells, as no higher molecular weight Cys-C or β2M bands are detected after treatment^[1]. NV914 (6-24 μM; 24 h) induces readthrough of the UGA premature termination codon in pFLuc190UGA-transfected HeLa cells, and this activity is counteracted by FTSJ1 overexpression^[3]. NV914 (12 μM; 24 h) induces readthrough of the W1282X UGA premature termination codon in IB3.1 cystic fibrosis cells, and this activity is reduced by FTSJ1 overexpression^[3].

References:
[1]. Perriera R, et al. Readthrough Approach Using NV Translational Readthrough-Inducing Drugs (TRIDs): A Study of the Possible Off-Target Effects on Natural Termination Codons (NTCs) on TP53 and Housekeeping Gene Expression. Int J Mol Sci. 2023;24(20):15084. Published 2023 Oct 11.
[2]. Corrao F, et al. Nonsense codons suppression. An acute toxicity study of three optimized TRIDs in murine model, safety and tolerability evaluation. Biomed Pharmacother. 2022;156:113886.
[3]. Carollo PS, et al. Investigating the Inhibition of FTSJ1, a Tryptophan tRNA-Specific 2'-O-Methyltransferase by NV TRIDs, as a Mechanism of Readthrough in Nonsense Mutated CFTR. Int J Mol Sci. 2023;24(11):9609. Published 2023 Jun 1.