SRI-41315, a chemical compound, effectively addresses premature termination codons (PTCs) associated with cystic fibrosis in immortalized and primary human bronchial epithelial cells. It induces a prolonged pause at stop codons, resulting in the restoration of cystic fibrosis transmembrane conductance regulator (CFTR) expression and function. This compound achieves PTC suppression by reducing the abundance of the termination factor eRF1. Additionally, SRI-41315 synergistically enhances CFTR activity by potentiating aminoglycoside-mediated readthrough [1].

SRI-41315 exhibits target cell cytotoxicity (CC50) values >50 μM in both FRT and 16BE14o- cells [1]. SRI-41315 shows improved potency and efficacy in FRT cells that translated to 16HBE14o- cells [1]. SRI-41315 (5 μM, 20 h) depletes eRF1 levels through a proteasome-mediated degradation pathway [1]. Western Blot Analysis [1] Cell Line: CFTR-G542X 16HBEge G542X cells Concentration: 5 μM Incubation Time: 20 h Result: Depleted eRF1 levels through a proteasome-mediated degradation pathway. SRI-41315-mediated eRF1 degradation was prevented by the addition of (S)-MG132 but not the neddylation inhibitor MLN4924.