Small molecule inhibition of phosphatidylinositol-3,4,5-triphosphate (PIP3) binding to pleckstrin homology domains
Small molecule inhibition of phosphatidylinositol-3,4,5-triphosphate (PIP3) binding to pleckstrin homology domains
复制标题
DOI：
10.1073/pnas.1004522107
复制
发表时间：
2010-11-16
影响因子：
11.1
通讯作者：
Degterev, Alexei
中科院分区：
文献类型：
--
作者：
Miao, Benchun;Skidan, Igor;Degterev, Alexei
PI 3-激酶（PI 3 K）途径调节许多细胞过程，尤其是细胞代谢、细胞存活和凋亡。磷脂酰肌醇-3，4，5-三磷酸（PIP 3）是PI 3 K活性的产物和关键信号分子，其通过将含有普列克底物蛋白同源（PH）结构域的蛋白募集到细胞膜来起作用。在这里，我们描述了一个新的结构类的非磷酸肌醇小分子拮抗剂（PITenins，PIT）的PIP 3-PH结构域的相互作用（IC 50范围从13.4到31 μ M的PIP 3/Akt PH结构域结合试验）。PIT抑制许多PIP 3结合PH结构域的相互作用，包括Akt和PDK 1的相互作用，而不影响几个PIP 2选择性PH结构域。因此，PIT抑制PI 3 K-PDK 1-Akt通路并触发代谢应激和细胞凋亡。PIT-1类似物在体内显示出显著的抗肿瘤活性，包括抑制肿瘤生长和诱导细胞凋亡。总之，我们的研究证明了开发PIP 3信号传导的特异性小分子拮抗剂的可行性。
The PI3-kinase (PI3K) pathway regulates many cellular processes, especially cell metabolism, cell survival, and apoptosis. Phosphatidylinositol-3,4,5-trisphosphate (PIP3), the product of PI3K activity and a key signaling molecule, acts by recruiting pleckstrin-homology (PH) domain-containing proteins to cell membranes. Here, we describe a new structural class of nonphosphoinositide small molecule antagonists (PITenins, PITs) of PIP3-PH domain interactions (IC50 ranges from 13.4 to 31 mu M in PIP3/Akt PH domain binding assay). PITs inhibit interactions of a number of PIP3-binding PH domains, including those of Akt and PDK1, without affecting several PIP2-selective PH domains. As a result, PITs suppress the PI3K-PDK1-Akt pathway and trigger metabolic stress and apoptosis. A PIT-1 analog displayed significant antitumor activity in vivo, including inhibition of tumor growth and induction of apoptosis. Overall, our studies demonstrate the feasibility of developing specific small molecule antagonists of PIP3 signaling.