Novel PI analogues selectively block activation of the pro-survival serine/threonine kinase Akt
Novel PI analogues selectively block activation of the pro-survival serine/threonine kinase Akt
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DOI：
10.1021/ja0285159
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发表时间：
2003-02-05
影响因子：
15
通讯作者：
Dennis, PA
中科院分区：
文献类型：
--
作者：
Kozikowski, AP;Sun, HY;Dennis, PA
报道了从白坚木糖醇合成一系列3-脱氧醚脂型磷脂酰肌醇（PI）类似物，其选择性地阻断Akt和下游底物的活化，而不影响具有高水平组成性活性Akt的H157和H1703肺癌细胞中上游激酶PDK-1或下游其它激酶如MAPK的活化。这些化合物中的2-羟基被删除或烷基化，目的是阻止这些化合物被PI特异性磷脂酶C（PI-PLC）代谢降解。具有磷酸酯接头的PI类似物比具有碳酸酯接头的那些更有效。这些化合物对Akt的特异性抑制验证了靶向关键信号传导蛋白PH结构域的配体设计，从而提供了一类独特的可能的癌症治疗剂。
The synthesis froml-quebrachitol of a series of 3-deoxygenated ether lipid-type phosphatidylinositol (PI) analogues is reported, that selectively block activation of Akt and downstream substrates without affecting activation of the upstream kinase, PDK-1, or other kinases downstream ofrassuch as MAPK in H157 and H1703 lung cancer cells that have high levels of constitutively active Akt. The 2-hydroxyl in these compounds was deleted or alkylated with the intent to preclude metabolic degradation of these compounds by PI-specific phospholipase C (PI-PLC). PI analogues with phosphate linkers are more effective than those with carbonate linkers. Specific inhibition of Akt by these compounds validates ligand design targeted to the PH domains of crucial signaling proteins, thus providing a unique class of possible cancer therapeutics.