Kinase drug discovery--what's next in the field?
Kinase drug discovery--what's next in the field?
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DOI：
10.1021/cb300610s
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发表时间：
2013-01-18
影响因子：
4
通讯作者：
Alessi, Dario R.
中科院分区：
文献类型：
--
作者：
Cohen, Philip;Alessi, Dario R.
在过去的 15 年里，蛋白激酶已成为制药行业在癌症领域最重要的一类药物靶点。过去十年中，约有 20 种靶向激酶的药物已被批准用于临床，还有数百种药物正在进行临床试验。然而，最近批准的第一个用于治疗炎症性疾病的蛋白激酶抑制剂，加上对控制免疫系统的信号网络的深入了解，表明未来 10 年人们对这一领域的兴趣将会激增。在这方面，我们讨论了针对 MyD88 信号网络中的蛋白激酶来开发治疗慢性炎症和自身免疫性疾病的药物的机会。蛋白激酶的激活突变是许多其他疾病和病症的基础，我们还讨论了为什么蛋白激酶 SPAK/OSR1 和 LRRK2 最近分别成为治疗高血压和帕金森病的有趣靶标，以及开发 LRRK2 抑制剂所取得的进展。最后，我们建议更多地关注激酶激活抑制剂的鉴定，而不是激酶活性，可能会在鉴定信号转导级联的精确特异性抑制剂方面带来好处，并且我们还强调“假激酶”是药物开发中一个有吸引力且尚未探索的领域，在未来几年值得更多关注。
Over the past 15 years protein kinases have become the pharmaceutical industry’s most important class of drug target in the field of cancer. Some 20 drugs that target kinases have been approved for clinical use over the past decade, and hundreds more are undergoing clinical trials. However, the recent approval of the first protein kinase inhibitors for the treatment of inflammatory diseases, coupled with an enhanced understanding of the signaling networks that control the immune system, suggests that there will be a surge of interest in this area over the next 10 years. In this connection, we discuss opportunities for targeting protein kinases in the MyD88 signaling network for the development of drugs to treat chronic inflammatory and autoimmune diseases. Activating mutations in protein kinases underlie many other diseases and conditions, and we also discuss why the protein kinases SPAK/OSR1 and LRRK2 have recently become interesting targets for the treatment of hypertension and Parkinson’s disease, respectively, and the progress that has been made in developing LRRK2 inhibitors. Finally we suggest that more focus on the identification of inhibitors of kinase activation, rather than kinase activity, may pay dividends in identifying exquisitely specific inhibitors of signal transduction cascades, and we also highlight “pseudo-kinases” as an attractive and unexplored area for drug development that merits much more attention in the years to come.
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DOI：
10.1073/pnas.1203223109
发表时间：
2012-06-26
影响因子：
11.1
作者：
Gilsbach, Bernd K.;Ho, Franz Y.;Kortholt, Arjan
通讯作者：
Kortholt, Arjan
影响因子：
7.5
作者：
Cohen, Philip
通讯作者：
Cohen, Philip
脑渗透 LRRK2 抑制剂。
影响因子：
4.2
作者：
Choi, Hwan Geun;Zhang, Jinwei;Deng, Xianming;Hatcher, John M.;Patricelli, Matthew P.;Zhao, Zheng;Alessi, Dario R.;Gray, Nathanael S.
通讯作者：
Gray, Nathanael S.
影响因子：
4.8
作者：
ALESSI, DR;CUENDA, A;SALTIEL, AR
通讯作者：
SALTIEL, AR
影响因子：
7.3
作者：
Estrada, Anthony A.;Liu, Xingrong;Sweeney, Zachary K.
通讯作者：
Sweeney, Zachary K.