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首页> 外文期刊>Expert Opinion on Therapeutic Patents >Recent advances in the discovery of small-molecule ATP competitive mTOR inhibitors: a patent review
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Recent advances in the discovery of small-molecule ATP competitive mTOR inhibitors: a patent review

机译：小分子ATP竞争性mTOR抑制剂发现的最新进展：专利审查

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The mammalian target of rapamycin (mTOR) is a protein kinase and a key component of the PI3K/Akt/mTOR signaling pathway, and is deregulated in half of all human cancers. Rapamycin and its analogs (rapa-logs) are allosteric inhibitors of one functional mTOR complex, mTORCI, and are clinically proven therapeutic agents for the treatment of certain cancers. However, rapalogs mainly partially inhibit mTORCI, while ATP competitive inhibitors suppress both mTORCI and mT0RC2, and therefore may offer advantages in the clinic. Recently, small-molecule inhibitors have entered clinical trials that are mTOR-selective or dual mT0R/PI3K inhibitors. This review focuses on ATP-competitive mTOR inhibitors that have appeared in the patent literature in 2010. Many inhibitors with new structural motifs have been discovered as well as inhibitors that are related to previously disclosed structures. This review endeavors to put into perspective the diverse structural elements that make up these compounds. Patent applications are covered that include either selective mTOR inhibitors or dual mTOR/PI3K inhibitors. The PI3K/mTOR signaling pathway is an exciting target for the development of Pharmaceuticals to treat cancer and other diseases, due to the unique combination of a clinically and commercially validated pathway approach (i.e., rapalogs), combined with a biological rationale for further increased efficacy (i.e., ATP-competitive inhibitors). With the number of candidate drugs currently in development or at earlier stages of the drug discovery pipeline, we are bound to see small-molecule inhibitors reach pivotal trials, and hopefully the market, in the near future.
机译：雷帕霉素（mTOR）的哺乳动物靶标是一种蛋白激酶，是PI3K / Akt / mTOR信号通路的关键组成部分，在所有人类癌症的一半中均被放松调节。雷帕霉素及其类似物（rapa-logs）是一种功能性mTOR复合物mTORCI的变构抑制剂，并且是经临床证明的用于治疗某些癌症的治疗剂。但是，雷帕洛斯主要抑制mTORCI，而ATP竞争性抑制剂同时抑制mTORCI和mT0RC2，因此可能在临床上具有优势。最近，小分子抑制剂进入了mTOR选择性或双重mT0R / PI3K抑制剂的临床试验。这篇综述着重于2010年在专利文献中出现的具有ATP竞争性的mTOR抑制剂。发现了许多具有新结构基序的抑制剂以及与先前公开的结构相关的抑制剂。这篇综述致力于将构成这些化合物的各种结构元素透视化。涵盖包括选择性mTOR抑制剂或双重mTOR / PI3K抑制剂的专利申请。 PI3K / mTOR信号通路是治疗癌症和其他疾病的药物开发的激动人心的目标，这是由于临床和商业验证的通路方法（即rapalogs）的独特组合，并结合了生物学原理以进一步提高疗效（即ATP竞争性抑制剂）。随着目前正在开发中的候选药物的数量或在药物发现管线的早期阶段，我们必将看到小分子抑制剂在不久的将来达到关键性试验，并有望进入市场。

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