Characterization of pomiferin triacetate as a novel mTOR and translation inhibitor

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• 作者：Magdalena M. Bajer^a ; Michael M. Kunze^a ; Johanna S. Blees^a ; Heidi R. Bokesch^b ; ^c ; Hanyong Chen^e ; Thilo F. Brauß ; ^a ; Zigang Dong^e ; Kirk R. Gustafson^b ; Ricardo M. Biondi^f ; Curtis J. Henrich^b ; ^c ; James B. McMahon^b ; Nancy H. Colburn^d ; Tobias Schmid^a ; ¹ ; ^{t.schmid@biochem.uni-frankfurt.de" class="auth_mail} ; Bernhard Brü ; ne^a ; ¹
• 关键词：Mammalian target of rapamycin ; Natural product ; Translation ; Pomiferin triacetate
• 刊名：Biochemical Pharmacology
• 出版年：1 April, 2014
• 年：2014
• 卷：88
• 期：3
• 页码：313-321
• 全文大小：1394 K

文摘

Deregulation of the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR)-70 kDa ribosomal protein S6 kinase 1 (p70^S6K) pathway is commonly observed in many tumors. This pathway controls proliferation, survival, and translation, and its overactivation is associated with poor prognosis for tumor-associated survival. Current efforts focus on the development of novel inhibitors of this pathway. In a cell-based high-throughput screening assay of 15,272 pure natural compounds, we identified pomiferin triacetate as a potent stabilizer of the tumor suppressor programmed cell death 4 (Pdcd4). Mechanistically, pomiferin triacetate appeared as a general inhibitor of the PI3K-Akt-mTOR-p70^S6K cascade. Interference with this pathway occurred downstream of Akt but upstream of p70^S6K. Specifically, mTOR kinase emerged as the molecular target of pomiferin triacetate, with similar activities against mTOR complexes 1 and 2. In an in vitro mTOR kinase assay pomiferin triacetate dose-dependently inhibited mTOR with an IC₅₀ of 6.2 渭M. Molecular docking studies supported the interaction of the inhibitor with the catalytic site of mTOR. Importantly, pomiferin triacetate appeared to be highly selective for mTOR compared to a panel of 17 lipid and 50 protein kinases tested. As a consequence of the mTOR inhibition, pomiferin triacetate efficiently attenuated translation. In summary, pomiferin triacetate emerged as a novel and highly specific mTOR inhibitor with strong translation inhibitory effects. Thus, it might be an interesting lead structure for the development of mTOR- and translation-targeted anti-tumor therapies.