ArticleEMBO molecular medicine2023
Control of fibrosis with enhanced safety via asymmetric inhibition of prolyl-tRNA synthetase 1.
Article in EMBO molecular medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 23 citations in OpenAlex.
- Inhibition of prolyl-tRNA synthetase and efflux pumps as a dual-targeting strategy against multidrug-resistant bacteria.Journal of enzyme inhibition and medicinal chemistry · 2026Article
- Metabolic reprogramming in fibrosis-related diseases: underlying mechanisms and therapeutics.Molecular biomedicine · 2026Review
- Transforming growth factor-β1 downregulates tryptophanyl-tRNA synthetase expression in human lung fibroblasts.Advances in medical sciences · 2026Article
- Article
- The key enzyme PYCR1 in proline metabolism: a dual driver of cancer progression and fibrotic remodeling.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- Metabolic dysregulation in pulmonary fibrosis: insights into amino acid contributions and therapeutic potential.Cell death discovery · 2025Review
- Emerging Concepts in Therapeutic Interventions for Idiopathic Pulmonary Fibrosis.Seminars in respiratory and critical care medicine · 2025Review
- EPRS1-mediated fibroblast activation and mitochondrial dysfunction promote kidney fibrosis.Experimental & molecular medicine · 2024Article
- A Review of Antibacterial Candidates with New Modes of Action.ACS infectious diseases · 2024Review
- Emerging pharmacological options in the treatment of idiopathic pulmonary fibrosis (IPF).Expert review of clinical pharmacology · 2024Review
- Article
- Control of fibrosis with enhanced safety via asymmetric inhibition of prolyl-tRNA synthetase 1.EMBO molecular medicine · 2023Article
Corrections and comments
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Authors and funding
21 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Prolyl-tRNA synthetase 1 (PARS1) has attracted much interest in controlling pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases. However, there are concerns about its catalytic inhibition for potential adverse effects on global protein synthesis. We developed a novel compound, DWN12088, whose safety was validated by clinical phase 1 studies, and therapeutic efficacy was shown in idiopathic pulmonary fibrosis model. Structural and kinetic analyses revealed that DWN12088 binds to catalytic site of each protomer of PARS1 dimer in an asymmetric mode with different affinity, resulting in decreased responsiveness at higher doses, thereby expanding safety window. The mutations disrupting PARS1 homodimerization restored the sensitivity to DWN12088, validating negative communication between PARS1 promoters for the DWN12088 binding. Thus, this work suggests that DWN12088, an asymmetric catalytic inhibitor of PARS1 as a novel therapeutic agent against fibrosis with enhanced safety.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.