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Orthogonal assays for the identification of inhibitors of the single-stranded nucleic acid binding protein YB-1

Acta Pharmaceutica Sinica B 2019年第5期9卷 997-1007页

作者： Alexander J.Trevarton Yan Zhou Dehua Yang Gordon W.Rewcastle Jack U.Flanagan Antony Braithwaite Peter R.Shepherd Cristin G.Print Ming-Wei Wang annette lasham Department of Molecular Medicine and Pathology University of AucklandAucklandNew Zealand The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research Shanghai Institute of Materia MedicaChinese Academy of Sciences(CAS)Shanghai201203China Auckland Cancer Society Research Centre AucklandNew Zealand Maurice Wilkins Centre for Molecular Biodiscovery University of AucklandAucklandNew Zealand Department of Pathology Dunedin School of MedicineUniversity of OtagoDunedinNew Zealand Maurice Wilkins Centre for Molecular Biodiscovery University of OtagoDunedinNew Zealand School of Pharmacy Fudan UniversityShanghai201203China

We have previously shown that high expression of the nucleic acid binding factor YB-1 is strongly associated with poor prognosis in a variety of cancer types. The 3-dimensional protein structure of YB-1 has yet to be determined and its role in transcriptional regulation remains elusive. Drug targeting of transcription factors is often thought to be difficult and there are very few published high-throughput screening approaches. YB-1 predominantly binds to single-stranded nucleic acids, adding further difficulty to drug discovery. Therefore, we have developed two novel screening assays to detect compounds that interfere with the transcriptional activation properties of YB-1, both of which may be generalizable to screen for inhibitors of other nucleic acid binding molecules. The first approach is a cell-based luciferase reporter gene assay that measures the level of activation of a fragment of the E2 F1 promoter by YB-1. The second approach is a novel application of the Alpha Screen system, to detect interference of YB-1 interaction with a single-stranded DNA binding site. These complementary assays examine YB-1 binding to two discrete nucleic acid sequences using two different luminescent signal outputs and were employed sequentially to screen 7360 small molecule compounds leading to the identification of three putative YB-1 inhibitors.

关键词： Cancer YB-1 Luciferase Alpha Screen Transcription factor Single-stranded DNA

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