{"title":"Methods for profiling the target and off-target landscape of PARP inhibitors","authors":"Daniel S. Bejan, Michael S. Cohen","doi":"10.1016/j.crchbi.2022.100027","DOIUrl":null,"url":null,"abstract":"<div><p>PARP inhibitor development is on the rise as more PARP family members emerge as novel drug targets in diseases such as cancer, inflammation, and viral infection. Understanding a drug's mechanism of action and potential risks for toxicity requires proteome-wide characterization of both on- and off-target engagement. This review will highlight different methods to map out the protein interaction profile of a small molecule, using the clinically approved PARP inhibitors as a case study. The approaches discussed here will mainly focus on chemoproteomic workflows, using inhibitor bead-conjugates and photoaffinity labeling probes, but will also touch on the utility of biochemical assays. Collectively, these strategies have revealed new targets for PARP inhibitors beyond the expected PARP1/2, providing valuable insights for understanding mechanism of action, toxicity, and polypharmacology.</p></div>","PeriodicalId":72747,"journal":{"name":"Current research in chemical biology","volume":"2 ","pages":"Article 100027"},"PeriodicalIF":0.0000,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S266624692200009X/pdfft?md5=eef9a42217a59c9adbae10a8602b14e0&pid=1-s2.0-S266624692200009X-main.pdf","citationCount":"2","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current research in chemical biology","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S266624692200009X","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 2
Abstract
PARP inhibitor development is on the rise as more PARP family members emerge as novel drug targets in diseases such as cancer, inflammation, and viral infection. Understanding a drug's mechanism of action and potential risks for toxicity requires proteome-wide characterization of both on- and off-target engagement. This review will highlight different methods to map out the protein interaction profile of a small molecule, using the clinically approved PARP inhibitors as a case study. The approaches discussed here will mainly focus on chemoproteomic workflows, using inhibitor bead-conjugates and photoaffinity labeling probes, but will also touch on the utility of biochemical assays. Collectively, these strategies have revealed new targets for PARP inhibitors beyond the expected PARP1/2, providing valuable insights for understanding mechanism of action, toxicity, and polypharmacology.
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