SRI-41315 / Southern Research, The University of Alabama - LARVOL DELTA

Investigating the combinatorial effects of ACE-tRNAs and small molecules to suppress CF-causing nonsense mutations (NACFC 2025) - "Figure 1 (abstract 279): Simultaneous AZD-7648 and UbVa treatment enhances gene insertion in primary ABCs using the dual-vector strategy...Additionally, several small molecules with differing mechanisms of actions have been shown to readthrough PTCs, such as G418, PTC124, SRI-41315 and CC-90009... Currently, experiments to determine the optimal ACE-tRNA + small molecule combinations are being performed."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

Therapeutic Opportunities in Overcoming Premature Termination Codons in Epidermolysis Bullosa via Translational Readthrough. (PubMed, Cells) - "Preclinical and clinical studies with gentamicin have demonstrated restored type VII collagen and laminin-332 expression, leading to measurable clinical improvements. Parallel development of novel compounds-including aminoglycoside analogs (e.g., ELX-02), translation termination factor degraders (e.g., CC-90009, SRI-41315, SJ6986), tRNA post-transcriptional inhibitors (e.g., 2,6-diaminopurine, NV848), and nucleoside analogs (e.g., clitocine)-has expanded the therapeutic pipeline. Although challenges remain regarding toxicity, codon specificity, and variable protein restoration thresholds, continued advances in molecular targeting and combination therapies offer the potential to establish readthrough therapies as localized or systemic treatments addressing both cutaneous and extracutaneous disease manifestations in EB."

Journal • Review

Small molecules acting as eRF degraders differently rescue G542X and W1282X-CFTR function (ECFS 2025) - " 16HBE14o- cells with the G542X-CFTR mutation were treated for 24 h with different drug combinations containing CC-90009 (0.1 M) or SRI-41315 (15 M) with/without VX-809 (1 M), and ELX-02 (200 M), as a RT agent, or SMG1i (1 M), as a NMD inhibitor. The eRF3a degrader CC-90009 has a role in potentiating RT, since it is effective on G542X-CFTR in combination with ELX-02, while the eRF1 degrader SRI-41315 is particularly active on W1282X-CFTR together with SMG1i. These results suggest that eRF degraders have different involvement in RT and NMD mechanisms. This work was supported by: the Cystic Fibrosis Foundation (GALIET22I0), the Italian Cystic Fibrosis Foundation (FFC#9/2022 and GMRF#1/2024), and the Italian Ministry of Health (GR-2018-12367126)."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • GSPT1

Pharmacological rescue of CFTR premature termination codon (PTC) variants (NACFC 2024) - "Drugs that deplete translation termination release factors, such as eRF1 (depleted by SRI-41315) and eRF3 (degraded by CC-90009), are of particular interest...In G27X HNECs, we observed 17.1% WT CFTR rescue when elexacaftor/tezacaftor/ivacaftor (ETI) was added to the combination of CC-90009, G418, and SMG1i... CC-90009, G418, and SMG1i synergized to restore substantial G27X, G542X, R1158X, and W1282X CFTR activity but had negligible effect on E92X and Q890X CFTR. PTC CFTR-homozygous primary cells and cell lines are valuable tools to develop genotype-targeted, clinically relevant PTC readthrough and NMD-inhibiting agents."

BMI1

Determining the functional consequences of translational readthrough at common CFTR nonsense mutations (NACFC 2024) - "When we used other small-molecule compounds, such as SRI-41315 and ELX-02, to induce readthrough of G542X and G550X, we observed no major differences from the variants produced with G418-mediated readthrough. WT CFTR protein was produced upon readthrough of some CFTR PTC contexts used in this study (Y122X, Q493X, R553X, Y1092X). However, CFTR variant proteins were also created. Overall, readthrough at seven CF-causing PTCs yielded 12 variant CFTR protein possibilities."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

eRF1 degrader SRI-41315 triggers ribosome collision quality control responses (NACFC 2024) - "As SRI-41315-mediated eRF1 reduction was dependent on translation rates, RNF14, and RNF25, we conclude that eRF1 is participating in translation and that RQC is being triggered by ribosome collisions. Also, we have shown that SRI-41315 induces the ISR in a manner dependent on the ribosome collision-sensing ISR kinases GCN1/GCN2. The RSR was also activated upon SRI-41315 treatment and was dependent on the ribosome collision-sensing kinase ZAK."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • Targeted Protein Degradation • CFTR • EIF2A • EIF2S1

CFTR premature termination codon readthrough can be enhanced by a transcript-specific antisense oligonucleotide approach (NACFC 2024) - "We also investigated whether combining ASOs with PTC modulators such as aminoglycosides (G418, ELX-02) and eRF degraders (SRI-41315, CC-90009) enhances PTC readthrough. This study presents a new approach for enhancing specific PTC readthrough in CFTR using ASOs that target a sequence near PTCs. This approach has the potential to safely increase the efficacy of current PTC modulators without exacerbating transcriptome-wide undesired effects."

CFTR

Enhancing readthrough therapy for epidermolysis bullosa: The synergistic potential of SRI-41315 and gentamicin. (SID 2024) - No abstract available

The eRF1 degrader SRI-41315 acts as a molecular glue at the ribosomal decoding center. (PubMed, Nat Chem Biol) - "Retention of eRF1 on ribosomes by SRI-41315 leads to ribosome collisions, eRF1 ubiquitylation and a higher frequency of translation termination at near-cognate stop codons. Our findings reveal a new mechanism of release factor inhibition and additional implications for pharmacologically targeting eRF1."

Journal • Targeted Protein Degradation

eRF1 degrader SRI-41315 triggers the ribosome quality control E3 ligase network (NACFC 2023) - "Although eRF1 depletion upon SRI-41315 treatment depended completely on the proteasome, knockdown of the RQC E3 ligases only rescued approximately 50% of eRF1 levels, indicating that other unidentified E3 ligase(s) may also be involved in this pathway. This first phase of eRF1 reduction also depended on translation, consistent with eRF1’s participation in translation and RQC being triggered by ribosome collisions. although these collisions activate the RSR, cell viability was only modestly reduced."

Targeted Protein Degradation • CFTR • EIF2A • EIF2S1

Identifying the amino acid(s) inserted upon premature termination codon readthrough and their effect on CFTR functionality (NACFC 2023) - "When we used other small-molecule compounds such as SRI-41315 and ELX-02 to induce RT of G542X and G550X, we observed no major differences from the variants produced with G418-mediated RT. Our results indicate that the local PTC mRNA context greatly affects the identity and frequency of amino acid incorporation upon RT. We are examining the functionality of the CFTR variants created upon RT and whether they are susceptible to HEMT. Additionally, as we observed similar amino acid incorporation profiles for two different classes of RT compounds at two different CFTR PTCs, we conclude that it is not the RT agent but rather the local sequence context that serves as the major determinant of amino acid incorporation upon RT."