Abstract |
The leflunomide metabolite analog alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13) is a rationally-designed specific inhibitor of the TEC family protein tyrosine kinase, Bruton's tyrosine kinase (BTK) which plays an important role in platelet physiology by regulating the glycoprotein GPVI-FcRgamma-coupled collagen receptor signaling pathway. At low micromolar concentrations, LFM-A13 inhibited collagen-induced ultrastructural changes indicative of activation. LFM-A13 inhibited collagen (but not thrombin, TRAP-6, or ADP)-induced platelet aggregation in a concentration-dependent fashion with an IC50 value of 2.8 microM. LFM-A13 was not toxic to mice when administered systemically at dose levels ranging from 1 to 100 mg/kg. At nontoxic dose levels, LFM-A13 prolonged the tail bleeding times of mice and improved event-free survival in two mouse models of agonist-induced invariably fatal pulmonary thromboembolism. To our knowledge, LFM-A13 is the first anti-thrombotic agent which prevents platelet aggregation by inhibiting BTK.
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Authors | Fatih M Uckun, Alexei Vassilev, Steve Bartell, Yaguo Zheng, Sandeep Mahajan, Heather E Tibbles |
Journal | Leukemia & lymphoma
(Leuk Lymphoma)
Vol. 44
Issue 9
Pg. 1569-77
(Sep 2003)
ISSN: 1042-8194 [Print] United States |
PMID | 14565661
(Publication Type: Comparative Study, Journal Article)
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Chemical References |
- Amides
- Enzyme Inhibitors
- Fibrinolytic Agents
- LFM A13
- Nitriles
- Peptide Fragments
- Platelet Aggregation Inhibitors
- Platelet Membrane Glycoproteins
- Quinazolines
- Receptors, Collagen
- WHI P131
- platelet membrane glycoprotein VI
- thrombin receptor peptide (42-47)
- Adenosine Diphosphate
- Collagen
- Thromboplastin
- Protein-Tyrosine Kinases
- Agammaglobulinaemia Tyrosine Kinase
- BTK protein, human
- Btk protein, mouse
- JAK3 protein, human
- Jak3 protein, mouse
- Janus Kinase 3
- Thrombin
- Aspirin
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Topics |
- Adenosine Diphosphate
(pharmacology)
- Agammaglobulinaemia Tyrosine Kinase
- Amides
(pharmacology, therapeutic use)
- Animals
- Aspirin
(pharmacology, therapeutic use)
- Bleeding Time
- Catalytic Domain
(drug effects)
- Collagen
(antagonists & inhibitors, pharmacology, toxicity)
- Drug Design
- Drug Evaluation, Preclinical
- Enzyme Inhibitors
(pharmacology, therapeutic use)
- Fibrinolytic Agents
(pharmacology, therapeutic use)
- Humans
- Janus Kinase 3
- Male
- Mice
- Mice, Inbred ICR
- Nitriles
(pharmacology, therapeutic use)
- Peptide Fragments
(pharmacology)
- Platelet Activation
(drug effects)
- Platelet Aggregation
(drug effects)
- Platelet Aggregation Inhibitors
(pharmacology, therapeutic use)
- Platelet Membrane Glycoproteins
(drug effects, physiology)
- Protein-Tyrosine Kinases
(antagonists & inhibitors, chemistry)
- Pulmonary Embolism
(chemically induced, prevention & control)
- Quinazolines
(pharmacology, therapeutic use)
- Receptors, Collagen
(drug effects, physiology)
- Signal Transduction
(drug effects)
- Thrombin
(pharmacology)
- Thromboembolism
(chemically induced, prevention & control)
- Thromboplastin
(toxicity)
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