SU5416, a VEGF receptor inhibitor and ligand of the AHR, represents a new alternative for immunomodulation.
SU5416, a VEGF receptor inhibitor and ligand of the AHR, represents a new alternative for immunomodulation.
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DOI：
10.1371/journal.pone.0044547
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Bradfield CA
中科院分区：
文献类型：
--
作者：
Mezrich JD;Nguyen LP;Kennedy G;Nukaya M;Fechner JH;Zhang X;Xing Y;Bradfield CA
实验化合物SU5416作为抗癌剂一直到第三阶段临床试验，推测是因为它作为VEGFR-2抑制剂的活性，但结果不佳。在这里，我们表明，SU5416也是一种芳香烃受体(AHR)激动剂，具有独特的性质。与TCDD一样，SU5416也支持以AHR依赖的方式在树突状细胞等免疫相关群体中诱导吲哚胺2，3双加氧酶(IDO)，从而在体外产生调节性T细胞。这些特性使我们认为SU5416可能是治疗自身免疫性疾病和预防移植排斥反应的理想临床药物，这两个领域AHR的调节配体已经显示出希望。同时，AHR的激动性可能代表着抗癌药物的不良特征，因为调节性T细胞可以抑制癌细胞的清除，而AHR的激活可以导致异物代谢酶的上调，这可能会影响联合用药的半衰期。SU5416不仅以接近2，3，7，8-四氯二苯并-对二恶英的效力激活人类AHR，而且它还以类似的效力激活多态的小鼠受体亚型(由AHRD和Ahrb1等位基因编码)，这一发现很少被描述，可能对鉴定这种受体的真正内源性配体有意义。
The experimental compound SU5416 went as far as Phase III clinical trials as an anticancer agent, putatively because of its activity as a VEGFR-2 inhibitor, but showed poor results. Here, we show that SU5416 is also an aryl hydrocarbon receptor (AHR) agonist with unique properties. Like TCDD, SU5416 favors induction of indoleamine 2,3 dioxygenase (IDO) in immunologically relevant populations such as dendritic cells in an AHR-dependent manner, leading to generation of regulatory T-cells in vitro. These characteristics lead us to suggest that SU5416 may be an ideal clinical agent for treatment of autoimmune diseases and prevention of transplant rejection, two areas where regulatory ligands of the AHR have shown promise. At the same time, AHR agonism might represent a poor characteristic for an anticancer drug, as regulatory T-cells can inhibit clearance of cancer cells, and activation of the AHR can lead to upregulation of xenobiotic metabolizing enzymes that might influence the half-lives of co-administered chemotherapeutic agents. Not only does SU5416 activate the human AHR with a potency approaching 2,3,7,8-tetrachlorodibenzo-p-dioxin, but it also activates polymorphic murine receptor isoforms (encoded by the Ahrd and Ahrb1 alleles) with similar potency, a finding that has rarely been described and may have implications in identifying true endogenous ligands of this receptor.
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影响因子：
30.5
作者：
通讯作者：
--
影响因子：
2.9
作者：
Flegal, KM
通讯作者：
Flegal, KM
影响因子：
3.6
作者：
Flaveny, Colin A.;Murray, Iain A.;Perdew, Gary H.
通讯作者：
Perdew, Gary H.
DOI：
10.1073/pnas.190256997
发表时间：
2000-09-12
影响因子：
11.1
作者：
Lahvis, GP;Lindell, SL;Bradfield, CA
通讯作者：
Bradfield, CA
影响因子：
9.1
作者：
Freire Carvalho, Jozelio;Blank, Miri;Shoenfeld, Yehuda
通讯作者：
Shoenfeld, Yehuda