Chemical and Structural Strategies to Selectively Target mTOR Kinase.
Chemical and Structural Strategies to Selectively Target mTOR Kinase.
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DOI：
10.1002/cmdc.202100332
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发表时间：
2021-09-16
期刊：
影响因子：
3.4
通讯作者：
Wymann MP
中科院分区：
文献类型：
--
作者：
Borsari C;De Pascale M;Wymann MP
雷帕霉素（mTOR）通路机制靶点的失调与癌症和神经系统疾病有关，这表明抑制mTOR是治疗多种人类疾病的有希望的策略。第一代mTOR抑制剂包括雷帕霉素及其类似物（rapalogs），它们作为TORC1的变构抑制剂。结构无关，直接靶向mTOR催化位点的ATP竞争性抑制剂可抑制TORC1和TORC2。在这里，我们回顾了为开发高选择性ATP竞争性mTOR激酶抑制剂（TORKi）而探索的化学支架的研究。广泛的药物化学活动使mTOR和磷酸肌肽3激酶（PI3K）家族之间结构相似性的挑战得以克服。TORKi涵盖了化学领域的广泛领域。在这里，化学取代和物理化学性质的研究揭示了化合物穿过血脑屏障（BBB）的能力。这项工作提供了支持优化TORKi治疗癌症和中枢神经系统疾病的见解。揭示mTOR激酶抑制剂的概况：在这里，我们概述了驱动mTOR对pi3k的效力和选择性的化学特征。化合物覆盖了广泛的化学空间进行了检查，特别强调模块接合的mTOR催化位点的不同结合区域。理化性质分析能够阐明影响ATP竞争性mTOR抑制剂脑渗透的描述符。
Dysregulation of the mechanistic target of rapamycin (mTOR) pathway is implicated in cancer and neurological disorder, which identifies mTOR inhibition as promising strategy for the treatment of a variety of human disorders. First‐generation mTOR inhibitors include rapamycin and its analogues (rapalogs) which act as allosteric inhibitors of TORC1. Structurally unrelated, ATP‐competitive inhibitors that directly target the mTOR catalytic site inhibit both TORC1 and TORC2. Here, we review investigations of chemical scaffolds explored for the development of highly selective ATP‐competitive mTOR kinase inhibitors (TORKi). Extensive medicinal chemistry campaigns allowed to overcome challenges related to structural similarity between mTOR and the phosphoinositide 3‐kinase (PI3K) family. A broad region of chemical space is covered by TORKi. Here, the investigation of chemical substitutions and physicochemical properties has shed light on the compounds’ ability to cross the blood brain barrier (BBB). This work provides insights supporting the optimization of TORKi for the treatment of cancer and central nervous system disorders. Unraveling the profile of mTOR kinase inhibitors: Herein, we outline the chemical features driving potency and selectivity for mTOR over PI3Ks. Compounds covering a broad chemical space are examined, with particular emphasis on the modules engaging the different binding regions of the mTOR catalytic site. Physicochemical property analysis enabled to shed light on the descriptors influencing the brain penetration of ATP‐competitive mTOR inhibitors.
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DOI：
10.1021/ci034205d
发表时间：
2004-01-01
期刊：
JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES
影响因子：
--
作者：
Adenot, M;Lahana, R
通讯作者：
Lahana, R
影响因子：
11.4
作者：
Brunn, GJ;Williams, J;Abraham, RT
通讯作者：
Abraham, RT
影响因子：
4.2
作者：
Burger, Matthew T.;Pecchi, Sabina;Voliva, Charles F.
通讯作者：
Voliva, Charles F.
影响因子：
15
作者：
Ding, S;Gray, NS;Schultz, PG
通讯作者：
Schultz, PG
影响因子：
4.2
作者：
Borsari, Chiara;Rageot, Denise;Wymann, Matthias P.
通讯作者：
Wymann, Matthias P.