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The anti-leukemic Bruton's tyrosine kinase inhibitor alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl) propenamide (LFM-A13) prevents fatal thromboembolism.

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.
AuthorsFatih M Uckun, Alexei Vassilev, Steve Bartell, Yaguo Zheng, Sandeep Mahajan, Heather E Tibbles
JournalLeukemia & lymphoma (Leuk Lymphoma) Vol. 44 Issue 9 Pg. 1569-77 (Sep 2003) ISSN: 1042-8194 [Print] United States
PMID14565661 (Publication Type: Comparative Study, Journal Article)
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
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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