ArticleInflammation research : official journal of the European Histamine Research Society ... [et al.]2023
BI 1291583: a novel selective inhibitor of cathepsin C with superior in vivo profile for the treatment of bronchiectasis.
Article in Inflammation research : official journal of the European Histamine Research Society ... [et al.], 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 23 citations in OpenAlex.
- Safety, tolerability, pharmacokinetics and pharmacodynamics of HSK31858, a novel oral dipeptidyl peptidase-1 inhibitor, in healthy volunteers: An integrated phase 1, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose study.British journal of clinical pharmacology · 2025Trial
- Cathepsin C (dipeptidyl peptidase 1) inhibition in adults with bronchiectasis: AIRLEAF, a phase II randomised, double-blind, placebo-controlled, dose-finding study.The European respiratory journal · 2025Trial
- The dipeptidyl peptidase 1 inhibition landscape in bronchiectasis and its future direction.European respiratory review : an official journal of the European Respiratory Society · 2026Review
- Age-Specific Considerations in Bronchiectasis Management: Focus on Older Adults with Emphasis on Anti-inflammatory Treatment.Drugs & aging · 2026Review
- Phase III AIRTIVITY study design: verducatib (BI 1291583) in people with bronchiectasis.ERJ open research · 2026Article
- Targeting Cathepsin C in Cancer Metastasis: Protease Network Activation, Inflammatory Crosstalk, and Therapeutic Opportunities.International journal of molecular sciences · 2026Review
- The Role of Dipeptidyl Peptidase Inhibitors in Pulmonary Diseases.Biomedicines · 2026Review
- Neutrophil extracellular traps in the tumor microenvironment, metastasis, therapy, and beyond: advances, challenges, and perspectives.Journal of hematology & oncology · 2026Review
- Brensocatib-Another Therapeutic "Window of Opportunity" for Patients with Bronchiectasis.Journal of clinical medicine · 2026Review
- Long-term reductions in inflammation in people with cystic fibrosis treated with elexacaftor/tezacaftor/ivacaftor.Annals of the American Thoracic Society · 2026Observational
- Tackling Neutrophilic Inflammation in Bronchiectasis: From Macrolides to Cathepsin C Inhibitors.Journal of inflammation research · 2026Review
- Therapies for bronchiectasis: mechanisms and potential effects.Frontiers in immunology · 2026Review
- It's a Trap!-Potential of Cathepsins in NET Formation.International journal of molecular sciences · 2025Review
- Protective effects of neutrophil serine protease inhibition against ischemia-reperfusion injury in lung or heart transplantation.The FEBS journal · 2025Review
- Neutrophil-derived biomarkers in bronchiectasis: identifying a common therapeutic target.The European respiratory journal · 2025Review
- Dipeptidyl peptidase 1 inhibitors and neutrophilic inflammation in bronchiectasis: a narrative review.Journal of thoracic disease · 2025Review
- Dipeptidyl peptidase-1 inhibitors in bronchiectasis.European respiratory review : an official journal of the European Respiratory Society · 2025Review
- Targeting neutrophil serine proteases in bronchiectasis.The European respiratory journal · 2025Review
- Dipeptidyl peptidase 1 inhibitors for inflammatory respiratory diseases: mechanisms, clinical trials, and therapeutic prospects.Frontiers in pharmacology · 2025Review
- Neutrophil-Derived Proteases in Lung Inflammation: Old Players and New Prospects.International journal of molecular sciences · 2024Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundAirway inflammation in chronic inflammatory lung diseases (e.g. bronchiectasis) is partly mediated by neutrophil-derived serine protease (NSP)/antiprotease imbalance. NSPs are activated during neutrophil myelopoiesis in bone marrow by cathepsin C (CatC; DPP1). CatC is therefore an attractive target to reduce NSP activity in the lungs of patients with bronchiectasis, restoring the protease/antiprotease balance. We report results from the preclinical pharmacological assessment of the novel CatC inhibitor BI 1291583.
methodsBinding kinetics of BI 1291583 to human CatC were determined by surface plasmon resonance. In vitro inhibition of human CatC activity was determined by CatC-specific fluorescent assay, and selectivity was assessed against related cathepsins and unrelated proteases. Inhibition of NSP neutrophil elastase (NE) production was assessed in a human neutrophil progenitor cell line. In vivo inhibition of NE and NSP proteinase 3 (PR3) in bronchoalveolar lavage fluid (BALF) neutrophils after lipopolysaccharide (LPS) challenge and distribution of BI 1291583 was determined in a mouse model.
resultsBI 1291583 bound human CatC in a covalent, reversible manner, selectively and fully inhibiting CatC enzymatic activity. This inhibition translated to concentration-dependent inhibition of NE activation in U937 cells and dose-dependent, almost-complete inhibition of NE and PR3 activity in BALF neutrophils in an in vivo LPS-challenge model in mice. BI 1291583 exhibited up to 100 times the exposure in the target tissue bone marrow compared with plasma.
conclusionBI 1291583-mediated inhibition of CatC is expected to restore the protease-antiprotease balance in the lungs of patients with chronic airway inflammatory diseases such as bronchiectasis.
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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.