Apogee Biotechnology Corporation, Hummelstown, PA 17036, USA.
J Pharmacol Exp Ther. 2010 Apr;333(1):129-39. doi: 10.1124/jpet.109.163444. Epub 2010 Jan 8.
Sphingolipid-metabolizing enzymes control the dynamic balance of the cellular levels of important bioactive lipids, including the apoptotic compound ceramide and the proliferative compound sphingosine 1-phosphate (S1P). Many growth factors and inflammatory cytokines promote the cleavage of sphingomyelin and ceramide leading to rapid elevation of S1P levels through the action of sphingosine kinases (SK1 and SK2). SK1 and SK2 are overexpressed in a variety of human cancers, making these enzymes potential molecular targets for cancer therapy. We have identified an aryladamantane compound, termed ABC294640 [3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide], that selectively inhibits SK2 activity in vitro, acting as a competitive inhibitor with respect to sphingosine with a K(i) of 9.8 muM, and attenuates S1P formation in intact cells. In tissue culture, ABC294640 suppresses the proliferation of a broad panel of tumor cell lines, and inhibits tumor cell migration concomitant with loss of microfilaments. In vivo, ABC294640 has excellent oral bioavailability, and demonstrates a plasma clearance half-time of 4.5 h in mice. Acute and chronic toxicology studies indicate that ABC294640 induces a transient minor decrease in the hematocrit of rats and mice; however, this normalizes by 28 days of treatment. No other changes in hematology parameters, or gross or microscopic tissue pathology, result from treatment with ABC294640. Oral administration of ABC294640 to mice bearing mammary adenocarcinoma xenografts results in dose-dependent antitumor activity associated with depletion of S1P levels in the tumors and progressive tumor cell apoptosis. Therefore, this newly developed SK2 inhibitor provides an orally available drug candidate for the treatment of cancer and other diseases.
鞘脂代谢酶控制着包括凋亡化合物神经酰胺和增殖化合物鞘氨醇 1-磷酸（S1P）在内的重要生物活性脂质的细胞水平的动态平衡。许多生长因子和炎性细胞因子促进神经鞘磷脂和神经酰胺的裂解，通过鞘氨醇激酶（SK1 和 SK2）的作用导致 S1P 水平的快速升高。SK1 和 SK2 在多种人类癌症中过度表达，使这些酶成为癌症治疗的潜在分子靶标。我们已经鉴定出一种芳基金刚烷化合物，称为 ABC294640 [3-(4-氯苯基)-金刚烷-1-羧酸（吡啶-4-基甲基）酰胺]，它在体外选择性抑制 SK2 活性，作为相对于鞘氨醇的竞争性抑制剂，其 K(i)为 9.8 μM，并在完整细胞中减弱 S1P 的形成。在组织培养中，ABC294640 抑制广泛的肿瘤细胞系的增殖，并抑制肿瘤细胞迁移，同时丧失微丝。在体内，ABC294640 具有良好的口服生物利用度，在小鼠中血浆清除半衰期为 4.5 小时。急性和慢性毒理学研究表明，ABC294640 会导致大鼠和小鼠的红细胞压积短暂轻微下降；然而，这种情况在治疗 28 天后会恢复正常。ABC294640 治疗不会导致血液学参数或大体或微观组织病理学的其他变化。ABC294640 口服给予荷乳腺癌异种移植瘤的小鼠可导致与 S1P 水平耗竭相关的剂量依赖性抗肿瘤活性，并伴有肿瘤细胞凋亡的进行性增加。因此，这种新开发的 SK2 抑制剂为治疗癌症和其他疾病提供了一种口服可用的候选药物。
