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Prevention of fatal thromboembolism in mice by selectively targeting Jak 3 kinase in platelets with 4- -amino-6,7-dimethoxyquinazoline



Prevention of fatal thromboembolism in mice by selectively targeting Jak 3 kinase in platelets with 4- -amino-6,7-dimethoxyquinazoline



Blood 96(11 Part 1): 273a, November 16



The quinazoline derivative, 4-(4'-Hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131) is a rationally designed specific inhibitor of Janus Kinase 3. We sought to determine the effects of WHI-P131 on platelet activation and aggregation in vitro as well as bleeding time and thromboplastin-induced fatal thromboembolism in vivo. At low micromolar concentrations, WHI-P131 inhibited thrombin-induced signaling events, including degranulation/serotonin release, membrane ruffling, pseudopod formation, and translocation of cytoplasmic proteins to the Tx-soluble and insoluble cytoskeleton. Thrombin-induced tyrosine phosphorylation as well as membrane localization of Stat 1 and Stat3beta were also markedly inhibited by WHI-P131. WHI-P131 inhibited thrombin-induced (but not collagen-induced) platelet aggregation with an IC50 value of 1.5 muM. Jak 3 deficient mice also exhibited a decrease in thrombin-induced platelet aggregation, overall tyrosine phosphorylation and phosphorylation of Stat 1 and Stat3beta. WHI-P131 was not toxic to mice when administered systemically at dose levels ranging from 1 mg/kg to 250 mg/kg. Highly effective platelet inhibitory plasma concentrations (gtoreq10 muM) of WHI-P131 could be achieved in mice without toxicity. At nontoxic dose levels, WHI-P131 prolonged the tail bleeding time of mice in dose-dependent manner and improved survival in a mouse model of thromboplastin-induced generalized and fatal thromboembolism. The probability of EFS after the thromboplastin challenge was 10+-7% (median survival time=2.5 min) for the vehicle-treated control group (N=20), 30+-15 (median survival time=5.3 min) for warfarin-treated control group (N=20) (P=0.001), and 30+-17% (median survival time =5.2 min) for the WHI-P131-treated test group (25 mg/kg dose level; N=10) (P=0.001) This present study significantly expands our knowledge of the importance of Jak3 and the Stat family proteins in platelets. To our knowledge, WHI-P131 is the first anti-thrombotic agent which prevents platelet aggregation by inhibiting Jak 3.

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Accession: 035551220

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