NV914

NV914 is an inhibitor of FTSJ1 (tryptophan tRNA-specific 2'-O-methyltransferase) that blocks the methyltransferase activity of FTSJ1. It induces the readthrough of premature stop codons, thereby allowing the synthesis of full-length proteins from genes carrying nonsense mutations. As a translation readthrough inducing compound (TRID), NV914 demonstrates readthrough activity for nonsense mutations in vitro without affecting natural stop codons, thus restoring CFTR protein expression. In mice, NV914 shows good acute oral tolerance, presenting low health risks and demonstrating favorable safety. NV914 is applicable in research related to cystic fibrosis and Shwachman-Diamond syndrome.

NV914, at concentrations of 3-48 μM for 24 hours, does not induce NTC readthrough in HCT116 cells, as evidenced by the absence of higher molecular weight p53 bands after treatment with Doxorubicin. Furthermore, when combined with Doxorubicin, NV914 does not alter the nuclear localization of p53 in HCT116 cells or impair its function, as determined by p21 mRNA expression levels. In 16HBE cells, at concentrations of 12-100 μM for 24 or 72 hours, NV914 does not induce NTC readthrough, indicated by the absence of higher molecular weight Cys-C or β2M bands post-treatment. However, NV914 at 6-24 μM for 24 hours can induce UGA stop codon readthrough in HeLa cells transfected with pFLuc190UGA, an effect diminished by FTSJ1 overexpression. In IB3.1 cystic fibrosis cells, NV914 at 12 μM for 24 hours can induce readthrough of the W1282X UGA stop codon, with decreased activity in the presence of FTSJ1 overexpression.

NV914 (2000 mg/kg; oral administration; single dose) demonstrates good tolerance in healthy C57BL/6 mice, showing only temporary signs of toxicity without significant organ damage. Consequently, it is classified as GHS category 5 (low health risk).