Korikani Meghana, Fathima Neeshat, Nadiminti Gouthami, Akula Sravani, Kancha Rama Krishna
Molecular Medicine and Therapeutics Laboratory, CPMB, Osmania University, Hyderabad 500007, India.
Molecular Medicine and Therapeutics Laboratory, CPMB, Osmania University, Hyderabad 500007, India.
Toxicol Appl Pharmacol. 2023 Apr 15;465:116469. doi: 10.1016/j.taap.2023.116469. Epub 2023 Mar 12.
Promiscuity of therapeutics has important implications in treatment and toxicity. So far, a comprehensive understanding of promiscuity related to kinase inhibitors is lacking and such an analysis may offer potential opportunities for drug repurposing. In the present study, profiling of inhibitor-specific kinases based on the available biochemical IC50s was performed, fold-change of IC50 values for additional targets were calculated by taking the primary target as the reference kinase, and finally the promiscuity degree (PD) for FDA-approved kinase inhibitors was calculated. Surprisingly, class II inhibitors showed more PD than that of the class I inhibitors. We further identified cancer types and sub-types in which additional kinase targets or off-targets of inhibitors were overexpressed for potential drug repurposing. In addition, the expression of these kinases in normal human tissues were also profiled to predict toxicity following drug repositioning. Taken together, the study offers opportunities for cancer treatment in a kinase-specific manner.
治疗药物的多效性在治疗和毒性方面具有重要意义。到目前为止，人们对激酶抑制剂相关的多效性缺乏全面的了解，而这样的分析可能为药物再利用提供潜在机会。在本研究中，基于可用的生化IC50对抑制剂特异性激酶进行了分析，以主要靶点作为参考激酶计算其他靶点IC50值的变化倍数，最后计算了FDA批准的激酶抑制剂的多效性程度（PD）。令人惊讶的是，II类抑制剂的PD比I类抑制剂更高。我们进一步确定了抑制剂的额外激酶靶点或脱靶在其中过度表达的癌症类型和亚型，以进行潜在的药物再利用。此外，还分析了这些激酶在正常人体组织中的表达，以预测药物重新定位后的毒性。综上所述，该研究为以激酶特异性方式进行癌症治疗提供了机会。
