ArticleThe Journal of biological chemistry2013
Characterization of a small molecule inhibitor of plasminogen activator inhibitor type 1 that accelerates the transition into the latent conformation.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 27 citations in OpenAlex.
- Review
- Identification and validation ofFrontiers in pharmacology · 2023Article
- PAI-1: A Major Player in the Vascular Dysfunction in Obstructive Sleep Apnea?International journal of molecular sciences · 2022Review
- PAI-1 in Diabetes: Pathophysiology and Role as a Therapeutic Target.International journal of molecular sciences · 2021Review
- A Narrative Review on Plasminogen Activator Inhibitor-1 and Its (Patho)Physiological Role: To Target or Not to Target?International journal of molecular sciences · 2021Review
- Structural Insight into the Two-Step Mechanism of PAI-1 Inhibition by Small Molecule TM5484.International journal of molecular sciences · 2021Article
- PAI-1, the Plasminogen System, and Skeletal Muscle.International journal of molecular sciences · 2020Review
- Molecular mechanism of two nanobodies that inhibit PAI-1 activity reveals a modulation at distinct stages of the PAI-1/plasminogen activator interaction.Journal of thrombosis and haemostasis : JTH · 2020Article
- Targeting PAI-1 in Cardiovascular Disease: Structural Insights Into PAI-1 Functionality and Inhibition.Frontiers in cardiovascular medicine · 2020Review
- Discovery and characterisation of an antibody that selectively modulates the inhibitory activity of plasminogen activator inhibitor-1.Scientific reports · 2019Article
- Characterization of the Annonaceous acetogenin, annonacinone, a natural product inhibitor of plasminogen activator inhibitor-1.Scientific reports · 2016Article
- uPA/uPAR and SERPINE1 in head and neck cancer: role in tumor resistance, metastasis, prognosis and therapy.Oncotarget · 2016Review
- Microwave-Assisted Synthesis of Bioactive Six-Membered Heterocycles and Their Fused Analogues.Molecules (Basel, Switzerland) · 2016Review
- Characterising the association of latency with α(1)-antitrypsin polymerisation using a novel monoclonal antibody.The international journal of biochemistry & cell biology · 2015Article
- Serpin latency transition at atomic resolution.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Functional stability of plasminogen activator inhibitor-1.TheScientificWorldJournal · 2014Review
- Mechanisms of thrombosis in obesity.Current opinion in hematology · 2013Review
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A novel class of small molecule inhibitors for plasminogen activator inhibitor type 1 (PAI-1), represented by AZ3976, was identified in a high throughput screening campaign. AZ3976 displayed an IC(50) value of 26 μm in an enzymatic chromogenic assay. In a plasma clot lysis assay, the compound was active with an IC(50) of 16 μm. Surprisingly, AZ3976 did not bind to active PAI-1 but bound to latent PAI-1 with a K(D) of 0.29 μm at 35 °C and a binding stoichiometry of 0.94, as measured by isothermal calorimetry. Reversible binding was confirmed by surface plasmon resonance direct binding experiments. The x-ray structure of AZ3976 in complex with latent PAI-1 was determined at 2.4 Å resolution. The inhibitor was bound in the flexible joint region with the entrance to the cavity located between α-helix D and β-strand 2A. A set of surface plasmon resonance experiments revealed that AZ3976 inhibited PAI-1 by enhancing the latency transition of active PAI-1. Because AZ3976 only had measurable affinity for latent PAI-1, we propose that its mechanism of inhibition is based on binding to a small fraction in equilibrium with active PAI-1, a latent-like prelatent form, from which latent PAI-1 is then generated more rapidly. This mode of action, with induced accelerated latency transition of active PAI-1 may, together with supporting x-ray data, provide improved opportunities for small molecule drug design in the hunt for therapeutically useful PAI-1 inhibitors.
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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.