Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance
Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance
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DOI：
10.1158/1535-7163.mct-16-0300
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发表时间：
2016-10-01
影响因子：
5.7
通讯作者：
Murray, Brion W.
中科院分区：
文献类型：
--
作者：
Chen, Ping;Lee, Nathan V.;Murray, Brion W.
从生物学角度来看，治疗性靶向异常细胞内激酶信号传导是有吸引力的，但药物开发通常受到毒性和疗效不足的阻碍。使用细胞和动物模型预测药物行为受到冗余激酶活性、缺乏独特底物和细胞特异性信号网络的干扰。细胞周期蛋白依赖性激酶（CDK）药物克服了这一现象，因为据报道，它们靶向共同的过程，但具有独特的临床活性。ATP竞争性CDK药物（dinaciclib、AG-024322、abemaciclib、palbociclib、ribociclib）的肿瘤细胞研究表明药理学相似，而未转化细胞中的分析表明存在显著差异。为了解决这种明显的脱节，药物行为在分子水平上进行了描述。非激酶结合研究和激酶组相互作用分析（重组和内源性激酶）显示，CDK家族以外的蛋白质似乎在dinaciclib/palbociclib/ribociclib药理学中几乎没有作用，可能对abemaciclib有贡献，并混淆了AG-024322分析。CDK 2和CDK 6与药物的共晶体结构鉴定了负责效力和激酶选择性的分子相互作用。与CDK的独特铰链结构的有效药物结合使得能够对大多数人激酶组具有选择性。CDK家族成员之间的选择性是通过与ATP结合口袋的非保守元件相互作用实现的。将临床药物暴露整合到分析中预测，palbociclib和ribociclib都是CDK 4/6抑制剂，abemaciclib抑制CDK 4/6/9，dinaciclib是广谱CDK抑制剂（CDK 2/3/4/6/9）。了解效力和选择性的分子组成也有助于合理设计未来几代激酶导向药物。(C)2016年AACR。
Therapeutically targeting aberrant intracellular kinase signaling is attractive from a biological perspective but drug development is often hindered by toxicities and inadequate efficacy. Predicting drug behaviors using cellular and animal models is confounded by redundant kinase activities, a lack of unique substrates, and cell-specific signaling networks. Cyclin-dependent kinase (CDK) drugs exemplify this phenomenon because they are reported to target common processes yet have distinct clinical activities. Tumor cell studies of ATP-competitive CDK drugs (dinaciclib, AG-024322, abemaciclib, palbociclib, ribociclib) indicate similar pharmacology while analyses in untransformed cells illuminates significant differences. To resolve this apparent disconnect, drug behaviors are described at the molecular level. Nonkinase binding studies and kinome interaction analysis (recombinant and endogenous kinases) reveal that proteins outside of the CDK family appear to have little role in dinaciclib/palbociclib/ribociclib pharmacology, may contribute for abemaciclib, and confounds AG-024322 analysis. CDK2 and CDK6 cocrystal structures with the drugs identify the molecular interactions responsible for potency and kinase selectivity. Efficient drug binding to the unique hinge architecture of CDKs enables selectivity toward most of the human kinome. Selectivity between CDK family members is achieved through interactions with nonconserved elements of the ATP-binding pocket. Integrating clinical drug exposures into the analysis predicts that both palbociclib and ribociclib are CDK4/6 inhibitors, abemaciclib inhibits CDK4/6/9, and dinaciclib is a broad-spectrum CDK inhibitor (CDK2/3/4/6/9). Understanding the molecular components of potency and selectivity also facilitates rational design of future generations of kinase-directed drugs. (C) 2016 AACR.