Chemical genetic discovery of targets and anti-targets for cancer polypharmacology.
Chemical genetic discovery of targets and anti-targets for cancer polypharmacology.
复制标题
DOI：
10.1038/nature11127
复制
发表时间：
2012-06-06
期刊：
影响因子：
64.8
通讯作者：
Cagan, Ross L.
中科院分区：
文献类型：
--
作者：
Dar, Arvin C.;Das, Tirtha K.;Shokat, Kevan M.;Cagan, Ross L.
癌症的复杂性导致最近对开发激酶抑制剂药物的多药理学方法的兴趣;然而，最佳激酶抑制谱仍然难以预测。使用Ret-kinase-driven果蝇模型的多发性内分泌肿瘤2型和kinome全药物分析，在这里，我们确定，AD 57拯救致癌的Ret诱导的致死性，而相关的Ret抑制剂赋予降低的疗效和增强的毒性。果蝇遗传学和化合物分析定义了三种途径，解释了疗效和剂量限制性毒性的机制基础。抑制Ret加Raf、Src和S6 K是最佳动物存活所需的，而抑制“抗靶”Tor由于释放负反馈而导致毒性。消除Tor结合的合理合成定制提供了AD 80和AD 81，其是在果蝇和哺乳动物多发性内分泌瘤2型模型中具有平衡的途径抑制、改善的功效和低毒性的化合物。结合激酶为重点的化学，激酶组广泛的分析和果蝇遗传学提供了一个强大的系统药理学方法，开发具有最大治疗指数的化合物。
The complexity of cancer has led to recent interest in polypharmacological approaches for developing kinase-inhibitor drugs; however, optimal kinase-inhibition profiles remain difficult to predict. Using a Ret-kinase-driven Drosophila model of multiple endocrine neoplasia type 2 and kinome-wide drug profiling, here we identify that AD57 rescues oncogenic Ret-induced lethality, whereas related Ret inhibitors imparted reduced efficacy and enhanced toxicity. Drosophila genetics and compound profiling defined three pathways accounting for the mechanistic basis of efficacy and dose-limiting toxicity. Inhibition of Ret plus Raf, Src and S6K was required for optimal animal survival, whereas inhibition of the ‘anti-target’ Tor led to toxicity owing to release of negative feedback. Rational synthetic tailoring to eliminate Tor binding afforded AD80 and AD81, compounds featuring balanced pathway inhibition, improved efficacy and low toxicity in Drosophila and mammalian multiple endocrine neoplasia type 2 models. Combining kinase-focused chemistry, kinome-wide profiling and Drosophila genetics provides a powerful systems pharmacology approach towards developing compounds with a maximal therapeutic index.
登录
查看更多内容
影响因子：
--
作者：
Mestres, Jordi;Gregori-Puigjane, Elisabet;Sole, Ricard V.
通讯作者：
Sole, Ricard V.
影响因子：
11.2
作者：
Vidal, Marcos;Warner, Stephen;Cagan, Ross L.
通讯作者：
Cagan, Ross L.
影响因子：
11.5
作者：
Ahmad, T;Eisen, T
通讯作者：
Eisen, T
影响因子：
5.3
作者：
Read, RD;Bach, EA;Cagan, RL
通讯作者：
Cagan, RL
影响因子：
2.7
作者：
Sawamoto, K;Okabe, M;Okano, H
通讯作者：
Okano, H