Uckun Fatih M, Vassilev Alexei, Bartell Steve, Zheng Yaguo, Mahajan Sandeep, Tibbles Heather E
Parker Hughes Cancer Center, Parker Hughes Institute, St. Paul, MN 55113, USA.
Leuk Lymphoma. 2003 Sep;44(9):1569-77. doi: 10.3109/10428190309178781.
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.
来氟米特代谢物类似物α-氰基-β-羟基-β-甲基-N-(2,5-二溴苯基)-丙烯酰胺(LFM-A13)是一种经过合理设计的TEC家族蛋白酪氨酸激酶布鲁顿酪氨酸激酶(BTK)的特异性抑制剂，BTK通过调节糖蛋白GPVI-FcRγ偶联的胶原受体信号通路在血小板生理过程中发挥重要作用。在低微摩尔浓度下，LFM-A13抑制了胶原诱导的表明激活的超微结构变化。LFM-A13以浓度依赖性方式抑制胶原(但不抑制凝血酶、TRAP-6或ADP)诱导的血小板聚集，IC50值为2.8微摩尔。当以1至100毫克/千克的剂量全身给药时，LFM-A13对小鼠无毒。在无毒剂量水平下，LFM-A13延长了小鼠的尾部出血时间，并改善了两种激动剂诱导的必死性肺血栓栓塞小鼠模型的无事件生存期。据我们所知，LFM-A13是第一种通过抑制BTK来预防血小板聚集的抗血栓药物。
