Dual kinase-bromodomain inhibitors for rationally designed polypharmacology
Dual kinase-bromodomain inhibitors for rationally designed polypharmacology
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DOI：
10.1038/nchembio.1471
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发表时间：
2014-04-01
影响因子：
14.8
通讯作者：
Knapp, Stefan
中科院分区：
文献类型：
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作者：
Ciceri, Pietro;Mueller, Susanne;Knapp, Stefan
同时抑制多种癌症驱动的激酶是提高靶向治疗的临床反应持久性的既定策略。然而，发现具有适当多靶点特征的激酶抑制剂的困难使得联合疗法的应用成为必要，这可能会构成重大的临床开发挑战。溴域家族的表观遗传读取域最近已成为癌症治疗的新靶点。在这里，我们报告了几种临床上的激酶抑制剂也抑制溴域，具有治疗相关的效力，最好被归类为双激酶-溴域抑制剂。BI-2536和TG-101348分别是临床上的PLK1和JAK2-Flt3激酶抑制剂，它们在BRD4上的纳摩尔活性特别值得注意，因为这些独立致癌途径上的活性组合例证了一种合理的单药多药靶向的新策略。此外，结构活性关系和共晶结构确定了设计特征，使得能够合理设计双激酶-溴结构域抑制剂的一般平台。
Concomitant inhibition of multiple cancer-driving kinases is an established strategy to improve the durability of clinical responses to targeted therapies. The difficulty of discovering kinase inhibitors with an appropriate multitarget profile has, however, necessitated the application of combination therapies, which can pose major clinical development challenges. Epigenetic reader domains of the bromodomain family have recently emerged as new targets for cancer therapy. Here we report that several clinical kinase inhibitors also inhibit bromodomains with therapeutically relevant potencies and are best classified as dual kinase-bromodomain inhibitors. Nanomolar activity on BRD4 by BI-2536 and TG-101348, which are clinical PLK1 and JAK2-FLT3 kinase inhibitors, respectively, is particularly noteworthy as these combinations of activities on independent oncogenic pathways exemplify a new strategy for rational single-agent polypharmacological targeting. Furthermore, structureactivity relationships and co-crystal structures identify design features that enable a general platform for the rational design of dual kinase-bromodomain inhibitors.