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哺乳动物雷帕霉素靶蛋白的 ATP 竞争性抑制剂：高活性和高选择性的吡唑并嘧啶的设计与合成。

ATP-competitive inhibitors of the mammalian target of rapamycin: design and synthesis of highly potent and selective pyrazolopyrimidines.

机构信息

Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA.

出版信息

J Med Chem. 2009 Aug 27;52(16):5013-6. doi: 10.1021/jm900851f.

DOI:10.1021/jm900851f
PMID:19645448
Abstract

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.

摘要

哺乳动物雷帕霉素靶蛋白（mTOR）是生长、存活和代谢的核心调节剂，是癌症治疗的有效靶点。雷帕霉素及其类似物是 mTOR 的变构抑制剂，只能部分抑制一种 mTOR 蛋白复合物。本文描述了具有增强抗癌疗效潜力的 ATP 竞争性、mTOR 全抑制剂。确定并改进了导致效力和选择性的结构特征，得到了在肿瘤异种移植模型中具有体内疗效的化合物。

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