Linking off-target kinase pharmacology to the differential cellular effects observed among PARP inhibitors
Linking off-target kinase pharmacology to the differential cellular effects observed among PARP inhibitors
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DOI：
10.18632/oncotarget.1814
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发表时间：
2014-05-01
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影响因子：
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通讯作者：
Mestres, Jordi
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文献类型：
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作者：
Antolin, Albert A.;Mestres, Jordi
PARP 抑制剂有望成为一类新型靶向抗癌药物。然而，根据最近的报告显示细胞效应存在显着差异，它们的真正作用机制仍然没有得到很好的了解。在这里，我们证明了三种 PARP 候选药物，即 rucaparib、veliparib 和 olaparib，在使用通过配体相似性关联蛋白质的计算方法选择的一组不同激酶中具有明显不同的体外亲和力特征。在这方面，rucaparib 以微摩尔亲和力抑制九种激酶，包括 PIM1、PIM2、PRKD2、DYRK1A、CDK1、CDK9、HIPK2、CK2 和 ALK。相比之下，奥拉帕尼不会抑制所测试的十六种激酶中的任何一种。在这两者之间，veliparib 仅抑制两种，即 PIM1 和 CDK9。在 PARP 抑制剂中观察到的差异激酶药理学为其不同的细胞效应提供了合理的解释，并为此类药物提供了未经探索的机会，但也提醒人们将临床前和临床结果从一种 PARP 候选药物直接转移到另一种药物的相关风险。
PARP inhibitors hold promise as a novel class of targeted anticancer drugs. However, their true mechanism of action is still not well understood following recent reports that show marked differences in cellular effects. Here, we demonstrate that three PARP drug candidates, namely, rucaparib, veliparib, and olaparib, have a clearly different in vitro affinity profile across a panel of diverse kinases selected using a computational approach that relates proteins by ligand similarity. In this respect, rucaparib inhibits nine kinases with micromolar affinity, including PIM1, PIM2, PRKD2, DYRK1A, CDK1, CDK9, HIPK2, CK2, and ALK. In contrast, olaparib does not inhibit any of the sixteen kinases tested. In between, veliparib inhibits only two, namely, PIM1 and CDK9. The differential kinase pharmacology observed among PARP inhibitors provides a plausible explanation to their different cellular effects and offers unexplored opportunities for this drug class, but alerts also on the risk associated to transferring directly both preclinical and clinical outcomes from one PARP drug candidate to another.