ATP-Competitive Inhibitors of the Mammalian Target of Rapamycin: Design and Synthesis of Highly Potent and Selective Pyrazolopyrimidines

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• 作者：Arie Zask ; Jeroen C. Verheijen ; Kevin Curran ; Joshua Kaplan ; David J. Richard ; Pawel Nowak ; David J. Malwitz ; Natasja Brooijmans ; Joel Bard ; Kristine Svenson ; Judy Lucas ; Lourdes Toral-Barza ; Wei-Guo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：August 27, 2009
• 年：2009
• 卷：52
• 期：16
• 页码：5013-5016
• 全文大小：732K
• 年卷期：v.52,no.16(August 27, 2009)
• ISSN：1520-4804

文摘

The mammalian target of rapamycin (mTOR), a central regulator of growth, survival, and metabolism, is a validated target for cancer therapy. Rapamycin and its analogues, allosteric inhibitors of mTOR, only partially inhibit one mTOR protein complex. ATP-competitive, global inhibitors of mTOR that have the potential for enhanced anticancer efficacy are described. Structural features leading to potency and selectivity were identified and refined leading to compounds with in vivo efficacy in tumor xenograft models.