title: 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.
authors.affiliation: Parker Hughes Cancer Center, Parker Hughes Institute, St. Paul, MN 55113, USA. fatih_uckun@ih.org
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
authors.forename: Alexei
authors.initials: A
authors.lastname: Vassilev
authors.forename: Steve
authors.initials: S
authors.lastname: Bartell
authors.forename: Yaguo
authors.initials: Y
authors.lastname: Zheng
authors.forename: Sandeep
authors.initials: S
authors.lastname: Mahajan
authors.forename: Heather E
authors.initials: HE
authors.lastname: Tibbles
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use; D001760:Bleeding Time; D020134:Catalytic Domain / Q000187:drug effects; D003094:Collagen / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000633:toxicity; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D053616:Janus Kinase 3; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010980:Platelet Membrane Glycoproteins / Q000187:drug effects / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011655:Pulmonary Embolism / Q000139:chemically induced / Q000517:prevention & control*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D038981:Receptors, Collagen / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology; D013923:Thromboembolism / Q000139:chemically induced / Q000517:prevention & control*; D013925:Thromboplastin / Q000633:toxicity
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; C118451:LFM A13; D009570:Nitriles; D010446:Peptide Fragments; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011799:Quinazolines; D038981:Receptors, Collagen; C116180:WHI P131; C098341:platelet membrane glycoprotein VI; C082835:thrombin receptor peptide (42-47); D000244:Adenosine Diphosphate; D003094:Collagen; D013925:Thromboplastin; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3; D013917:Thrombin; D001241:Aspirin