S32826, A Nanomolar Inhibitor of Autotaxin: Discovery, Synthesis and Applications as a Pharmacological Tool
S32826, A Nanomolar Inhibitor of Autotaxin: Discovery, Synthesis and Applications as a Pharmacological Tool
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DOI：
10.1124/jpet.108.141911
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发表时间：
2008-12-01
影响因子：
3.5
通讯作者：
Boutin, Jean A.
中科院分区：
文献类型：
--
作者：
Ferry, Gilles;Moulharat, Natacha;Boutin, Jean A.
自分泌运动因子催化溶血磷脂酰胆碱转化为溶血磷脂酸（LPA）。LPA是一种具有大量活性的磷脂，特别是作为运动因子或作为生长信号，通过其G蛋白偶联的七个跨膜受体。间接证据强烈表明，自分泌运动因子是主要的，如果不是唯一的循环LPA的来源。由于自分泌运动因子在肿瘤和糖尿病/肥胖等病理条件中的核心作用，其生物化学性质引起了广泛关注，但其在病理学中的作用的确认仍然是难以捉摸的。验证和/或确认其核心作用的一种方法是找到有效和选择性的抑制剂。使用比色测定并利用自分泌运动因子的磷酸二酯酶活性（其需要酶促位点而不是LPA生成）对数千种化合物进行系统筛选，发现了一种有效的纳摩尔抑制剂[4-（十四酰氨基）苄基]膦酸（S32826）。使用测量[C-14]溶血磷脂酰胆碱转化为[C-14] LPA的测定，该化合物对各种自分泌运动因子亚型具有抑制作用。我们还评估了S32826在糖尿病和肿瘤细胞模型中的活性。然而，该化合物的体内稳定性和/或生物利用度差，不允许将其用于动物。S32826是第一个报道的自分泌运动因子抑制剂，其IC 50在纳摩尔范围内，可用于验证自分泌运动因子在细胞模型中各种病理学中的作用。
Autotaxin catalyzes the transformation of lyso-phosphatidylcholine in lyso-phosphatidic acid (LPA). LPA is a phospholipid possessing a large panel of activity, in particular as a motility factor or as a growth signal, through its G-protein coupled seven transmembrane receptors. Indirect evidence strongly suggests that autotaxin is the main, if not the only source of circulating LPA. Because of its central role in pathologic conditions, such as oncology and diabetes/obesity, the biochemical properties of autotaxin has attracted a lot of attention, but confirmation of its role in pathology remains elusive. One way to validate and/or confirm its central role, is to find potent and selective inhibitors. A systematic screening of several thousand compounds using a colorimetric assay and taking advantage of the phosphodiesterase activity of autotaxin that requires the enzymatic site than for LPA generation, led to the discovery of a potent nanomolar inhibitor, [4-(tetradecanoylamino)benzyl]phosphonic acid (S32826). This compound was inhibitory toward the various autotaxin isoforms, using an assay measuring the [C-14] lyso-phosphatidylcholine conversion into [C-14] LPA. We also evaluated the activity of S32826 in cellular models of diabesity and oncology. Nevertheless, the poor in vivo stability and/or bioavailability of the compound did not permit to use it in animals. S32826 is the first reported inhibitor of autotaxin with an IC50 in the nanomolar range that can be used to validate the role of autotaxin in various pathologies in cellular models.