Department of Data Science, The Institute of Cancer Research, London, SM2 5NG, UK.
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, SM2 5NG, UK.
Sci Rep. 2020 Feb 17;10(1):2585. doi: 10.1038/s41598-020-59074-4.
Polypharmacology plays an important role in defining response and adverse effects of drugs. For some mechanisms, experimentally mapping polypharmacology is commonplace, although this is typically done within the same protein class. Four PARP inhibitors have been approved by the FDA as cancer therapeutics, yet a precise mechanistic rationale to guide clinicians on which to choose for a particular patient is lacking. The four drugs have largely similar PARP family inhibition profiles, but several differences at the molecular and clinical level have been reported that remain poorly understood. Here, we report the first comprehensive characterization of the off-target kinase landscape of four FDA-approved PARP drugs. We demonstrate that all four PARP inhibitors have a unique polypharmacological profile across the kinome. Niraparib and rucaparib inhibit DYRK1s, CDK16 and PIM3 at clinically achievable, submicromolar concentrations. These kinases represent the most potently inhibited off-targets of PARP inhibitors identified to date and should be investigated further to clarify their potential implications for efficacy and safety in the clinic. Moreover, broad kinome profiling is recommended for the development of PARP inhibitors as PARP-kinase polypharmacology could potentially be exploited to modulate efficacy and side-effect profiles.
多药理学在确定药物的反应和不良反应方面起着重要作用。对于某些机制，实验性地绘制多药理学图谱已经很常见，尽管这通常是在同一蛋白质类内进行的。四种 PARP 抑制剂已被 FDA 批准为癌症治疗药物，但缺乏一种精确的机制原理来指导临床医生为特定患者选择哪种药物。这四种药物对 PARP 家族的抑制谱大致相似，但在分子和临床水平上有几个报道的差异仍未得到很好的理解。在这里，我们报告了首次对四种 FDA 批准的 PARP 药物的非靶标激酶图谱进行全面表征。我们证明，所有四种 PARP 抑制剂在激酶组中都具有独特的多药理学特征。尼拉帕尼和鲁卡帕尼以临床可达到的亚微摩尔浓度抑制 DYRK1s、CDK16 和 PIM3。这些激酶代表迄今为止鉴定出的 PARP 抑制剂中最有效的非靶标抑制剂，应该进一步研究以阐明它们在临床疗效和安全性方面的潜在意义。此外，强烈建议对 PARP 抑制剂进行广泛的激酶组分析，因为 PARP-激酶的多药理学可能被用来调节疗效和副作用谱。
