دورية أكاديمية
Discovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays.
العنوان: | Discovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays. |
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المؤلفون: | Pierrat OA; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Liu M; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Collie GW; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK.; Division of Structural Biology, The Institute of Cancer Research, London, SW3 6JB, UK., Shetty K; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK.; Division of Structural Biology, The Institute of Cancer Research, London, SW3 6JB, UK., Rodrigues MJ; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK.; Division of Structural Biology, The Institute of Cancer Research, London, SW3 6JB, UK., Le Bihan YV; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK.; Division of Structural Biology, The Institute of Cancer Research, London, SW3 6JB, UK., Gunnell EA; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK.; Division of Structural Biology, The Institute of Cancer Research, London, SW3 6JB, UK., McAndrew PC; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Stubbs M; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Rowlands MG; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Yahya N; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Shehu E; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Talbot R; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Pickard L; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Bellenie BR; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Cheung KJ; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Drouin L; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Innocenti P; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Woodward H; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Davis OA; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Lloyd MG; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Varela A; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Huckvale R; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Broccatelli F; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Carter M; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Galiwango D; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Hayes A; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Raynaud FI; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Bryant C; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Whittaker S; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Rossanese OW; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Hoelder S; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., Burke R; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK., van Montfort RLM; Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, SM2 5NG, UK. rob.vanmontfort@icr.ac.uk.; Division of Structural Biology, The Institute of Cancer Research, London, SW3 6JB, UK. rob.vanmontfort@icr.ac.uk. |
المصدر: | Scientific reports [Sci Rep] 2022 Nov 03; Vol. 12 (1), pp. 18633. Date of Electronic Publication: 2022 Nov 03. |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: London : Nature Publishing Group, copyright 2011- |
مواضيع طبية MeSH: | Lymphoma, Large B-Cell, Diffuse*/pathology, Humans ; Crystallography, X-Ray ; Proto-Oncogene Proteins c-bcl-6/metabolism ; Drug Design ; Ligands |
مستخلص: | By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. As BCL6 deregulation is implicated in the development of Diffuse Large B-Cell Lymphoma, we sought to discover novel small molecule inhibitors that disrupt the BCL6-corepressor protein-protein interaction (PPI). Here we report our hit finding and compound optimisation strategies, which provide insight into the multi-faceted orthogonal approaches that are needed to tackle this challenging PPI with small molecule inhibitors. Using a 1536-well plate fluorescence polarisation high throughput screen we identified multiple hit series, which were followed up by hit confirmation using a thermal shift assay, surface plasmon resonance and ligand-observed NMR. We determined X-ray structures of BCL6 bound to compounds from nine different series, enabling a structure-based drug design approach to improve their weak biochemical potency. We developed a time-resolved fluorescence energy transfer biochemical assay and a nano bioluminescence resonance energy transfer cellular assay to monitor cellular activity during compound optimisation. This workflow led to the discovery of novel inhibitors with respective biochemical and cellular potencies (IC (© 2022. The Author(s).) |
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معلومات مُعتمدة: | 22897 United Kingdom CRUK_ Cancer Research UK; C309/A11566 United Kingdom CRUK_ Cancer Research UK |
المشرفين على المادة: | 0 (Proto-Oncogene Proteins c-bcl-6) 0 (Ligands) 0 (BCL6 protein, human) |
تواريخ الأحداث: | Date Created: 20221104 Date Completed: 20221107 Latest Revision: 20240210 |
رمز التحديث: | 20240210 |
مُعرف محوري في PubMed: | PMC9633773 |
DOI: | 10.1038/s41598-022-23264-z |
PMID: | 36329085 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2045-2322 |
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DOI: | 10.1038/s41598-022-23264-z |