Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability.
Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability.
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DOI：
10.1158/0008-5472.can-08-2058
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发表时间：
2008-11-15
期刊：
影响因子：
11.2
通讯作者：
Benjamin LE
中科院分区：
文献类型：
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作者：
Xue Q;Hopkins B;Perruzzi C;Udayakumar D;Sherris D;Benjamin LE
已经清楚的是，磷脂酰肌醇3-激酶（PI 3 K）/Akt/哺乳动物雷帕霉素靶（mTOR）途径对于促进肿瘤和肿瘤间质两者是中心的，并且因此是抗癌药物开发的主要靶标。第一代和第二代雷帕霉素类似物（原型mTOR抑制剂）已显示出前景，但由于mTOR信号传导的复杂性质，可能导致适得其反的反馈信号传导以增强上游Akt信号传导。我们提出了一种新的PI 3 K/Akt/mTOR抑制剂Palomid 529（P529），其抑制TORC 1和TORC 2复合物，并且在肿瘤和血管中类似地显示Akt信号传导和mTOR信号传导的抑制。我们发现P529抑制肿瘤生长、血管生成和血管通透性。它保留了雷帕霉素所拥有的肿瘤血管正常化的有益方面。然而，P529具有阻断pAktS 473信号传导的额外益处，这与阻断所有细胞中的TORC 2一致，从而绕过导致一些肿瘤细胞中Akt信号传导增加的反馈环。[Cancer Res 2008;68（22）：9551-7]
It has become clear that the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is central for promoting both tumor and tumor stroma and is therefore a major target for anticancer drug development. First- and second-generation rapalogs (prototypical mTOR inhibitors) have shown promise but, due to the complex nature of mTOR signaling, can result in counterproductive feedback signaling to potentiate upstream Akt signaling. We present a novel PI3K/Akt/mTOR inhibitor, Palomid 529 (P529), which inhibits the TORC1 and TORC2 complexes and shows both inhibition of Akt signaling and mTOR signaling similarly in tumor and vasculature. We show that P529 inhibits tumor growth, angiogenesis, and vascular permeability. It retains the beneficial aspects of tumor vascular normalization that rapamycin boasts. However, P529 has the additional benefit of blocking pAktS473 signaling consistent with blocking TORC2 in all cells and thus bypassing feedback loops that lead to increased Akt signaling in some tumor cells. [Cancer Res 2008;68(22):9551–7]