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Dual inhibition of PI3K and mTOR by VS-5584 suppresses thrombus formation

机译：通过VS-5584对PI3K和MTOR进行双重抑制抑制血栓形成

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摘要

VS-5584 is a highly selective dual kinase inhibitor which suppresses phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) activity. Because these kinases are crucially involved in primary hemostasis, we herein investigated the effect of this compound on thrombus formation in vitro and in vivo. Pretreatment of washed platelets (WP) or platelet-rich plasma (PRP) with VS-5584 inhibited the agonist-induced activation of surface glycoprotein complex (GP)IIb/IIIa and the upregulation of P-selectin. This was associated with a significantly reduced formation of platelet-leukocyte aggregates (PLA). VS-5584 further attenuated platelet aggregation and adhesion after agonist stimulation. In contrast, endothelial expression of intercellular adhesion molecule (ICAM)-1 and vascular cellular adhesion molecule (VCAM)-1 and secretion of von Willebrand Factor (vWF) were not affected by the dual kinase inhibitor. In vivo, VS-5584 inhibited photochemically induced thrombus formation as shown by a significantly prolonged time to complete vessel occlusion when compared to vehicle-treated controls. This was associated with an elevated tail vein bleeding time, indicating a potential hemorrhagic risk in VS-5584-treated mice. Taken together, these novel findings demonstrate that VS-5584 is a potent inhibitor of primary hemostasis targeting multiple platelet functions.
机译：VS-5584是一种高度选择性的双激酶抑制剂，其抑制磷脂酰肌醇3-激酶（PI3K）和哺乳动物的雷帕霉素（MTOR）活性靶标。因为这些激酶至关重要的是初级止血，所以我们在本文中研究了该化合物对体外和体内血栓形成的影响。用VS-5584的洗涤血小板（WP）或富含片富血小板的血浆（PRP）的预处理抑制了表面糖蛋白复合物（GP）IIB / IIIa的激动剂诱导的活化和P-选择素的上调。这与血小板白细胞聚集体（PLA）显着减少的形成有关。 VS-5584在激动剂刺激后进一步减弱血小板聚集和粘附性。相反，细胞间粘附分子（ICAM）-1和血管细胞粘附分子（VCAM）-1的内皮表达和von Willebrand因子（VWF）的分泌不受双激酶抑制剂的影响。在体内，VS-5584抑制了光化学诱导的血栓形成，如在与载体处理的对照相比时通过显着延长的时间来完成血管闭塞。这与尾静脉出血时间升高有关，表明VS-5584处理的小鼠中的潜在出血风险。在一起，这些新颖的研究结果表明，VS-5584是靶向多血小板功能的主要止血的有效抑制剂。

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