The small-molecule MERTK inhibitor UNC2025 decreases platelet activation and prevents thrombosis.
The small-molecule MERTK inhibitor UNC2025 decreases platelet activation and prevents thrombosis.
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DOI：
10.1111/jth.13875
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Di Paola JA
中科院分区：
文献类型：
--
作者：
Branchford BR;Stalker TJ;Law L;Acevedo G;Sather S;Brzezinski C;Wilson KM;Minson K;Lee-Sherick AB;Davizon-Castillo P;Ng C;Zhang W;Neeves KB;Lentz SR;Wang X;Frye SV;Shelton Earp H 3rd;DeRyckere D;Brass LF;Graham DK;Di Paola JA
Gas6 signals through the TAM (TYRO-3, AXL, MERTK) receptor family mediating platelet activation and thrombus formation via activation of the aggregate-stabilizing αIIbβ3 integrin. Here we describe anti-thrombotic effects mediated by UNC2025, a small molecule MERTK tyrosine kinase inhibitor. MERTK phosphorylation and downstream signaling were assessed by immunoblot. Light transmission aggregometry, flow cytometry, and microfluidic analysis were used to evaluate the impact of MERTK inhibition on platelet activation and stability of aggregate formation in vitro. The effects of MERTK inhibition on arterial and venous thrombosis, platelet accumulation at microvascular injury sites, and tail bleeding times were determined using murine models. The effects of combined treatment with ADP/P2Y1&12 pathway antagonists and UNC2025 were also evaluated. Treatment with UNC2025 inhibited MERTK phosphorylation and downstream activation of AKT and SRC, decreased platelet activation, and protected animals from pulmonary embolism and arterial thrombosis without increased bleeding times. The anti-platelet effect of UNC2025 was enhanced in combination with ADP/P2Y1&12 pathway antagonists and a greater-than-additive effect was observed when these two agents with different mechanisms of inhibition were co-administered. TAM kinase signaling represents a potential therapeutic target since inhibition of this axis, especially in combination with ADP/P2Y pathway antagonism, mediates decreased platelet activation, aggregate stability, and thrombus formation with less hemorrhagic potential compared to current treatment strategies. The data presented here also demonstrate anti-thrombotic activity mediated by UNC2025, a novel translational agent, and support development of TAM kinase inhibitors for clinical applications.
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DOI：
10.1158/1078-0432.ccr-16-1330
发表时间：
2017-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
DeRyckere D;Lee-Sherick AB;Huey MG;Hill AA;Tyner JW;Jacobsen KM;Page LS;Kirkpatrick GG;Eryildiz F;Montgomery SA;Zhang W;Wang X;Frye SV;Earp HS;Graham DK
通讯作者：
Graham DK
影响因子：
10.4
作者：
Cosemans, J. M. E. M.;Van Kruchten, R.;Heemskerk, J. W. M.
通讯作者：
Heemskerk, J. W. M.
影响因子：
2.9
作者：
Joo SJ
通讯作者：
Joo SJ
影响因子：
3.8
作者：
Hansen, Ryan R.;Wufsus, Adam R.;Barton, Steven T.;Onasoga, Abimbola A.;Johnson-Paben, Rebecca M.;Neeves, Keith B.
通讯作者：
Neeves, Keith B.
影响因子：
10.4
作者：
Gould, WR;Baxi, SM;Perrin, LA
通讯作者：
Perrin, LA