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Mechanistic studies of a small-molecule modulator of SMN2 splicing

2018; National Academy of Sciences; Volume: 115; Issue: 20 Linguagem: Inglês

10.1073/pnas.1800260115

1091-6490

Jingxin Wang, Peter G. Schultz, Kristen Johnson,

RNA modifications and cancer

Significance The development of small-molecule therapeutics that act by targeting defined DNA or RNA sequences associated with human disease remains a challenge. RG-7916, a small-molecule drug candidate for the treatment of spinal muscular atrophy (SMA), selectively regulates the alternative splicing (AS) of the SMN2 gene. Herein, we show that SMN-C2 and -C3, close analogs of RG-7916, act by binding SMN2 pre-mRNA and thereby increasing the affinity of the RNA binding proteins far upstream element binding protein 1 (FUBP1) and KH-type splicing regulatory protein (KHSRP) to the SMN2 pre-mRNA complex. These results suggest that nucleic acid targeted small molecules may have untapped potential for modulating disease processes at the level of pre-mRNA splicing.