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).) |
| References: | SLAS Discov. 2018 Jan;23(1):34-46. (PMID: 28957646) Acta Crystallogr D Biol Crystallogr. 2006 Jan;62(Pt 1):72-82. (PMID: 16369096) SLAS Discov. 2021 Sep;26(8):1020-1028. (PMID: 33899548) Mol Cell Biol. 2006 Sep;26(18):6880-9. (PMID: 16943429) Cancer Cell. 2007 Sep;12(3):280-92. (PMID: 17785208) Acta Crystallogr D Struct Biol. 2018 Feb 1;74(Pt 2):85-97. (PMID: 29533234) Nat Med. 2004 Dec;10(12):1329-35. (PMID: 15531890) Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42. (PMID: 21460441) Assay Drug Dev Technol. 2015 Jun;13(5):266-76. (PMID: 26107610) ACS Chem Biol. 2015 Aug 21;10(8):1797-804. (PMID: 26006698) J Med Chem. 2022 Jun 23;65(12):8169-8190. (PMID: 35657291) Cell. 2004 Oct 1;119(1):75-86. (PMID: 15454082) Sci China Life Sci. 2015 Dec;58(12):1226-32. (PMID: 26566802) J Med Chem. 2018 Sep 13;61(17):7573-7588. (PMID: 29969259) Leuk Lymphoma. 2008 May;49(5):874-82. (PMID: 18452090) J Clin Invest. 2016 Sep 1;126(9):3351-62. (PMID: 27482887) Bioorg Med Chem. 2017 Sep 1;25(17):4876-4886. (PMID: 28760529) Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21. (PMID: 20057044) Chem Soc Rev. 2013 Oct 21;42(20):7971-82. (PMID: 23864138) Nucleic Acids Res. 2007 Jul;35(Web Server issue):W375-83. (PMID: 17452350) J Biol Chem. 2021 Aug;297(2):100928. (PMID: 34274316) Cancer Cell. 2010 Apr 13;17(4):400-11. (PMID: 20385364) J Mol Recognit. 2005 Jul-Aug;18(4):273-81. (PMID: 15997470) PLoS One. 2014 Mar 04;9(3):e90889. (PMID: 24595451) Biochem Biophys Res Commun. 2017 Jan 8;482(2):310-316. (PMID: 27856253) J Med Chem. 2013 Jan 24;56(2):547-55. (PMID: 23234607) ACS Chem Biol. 2018 Nov 16;13(11):3131-3141. (PMID: 30335946) Cell Rep. 2017 Sep 19;20(12):2860-2875. (PMID: 28930682) J Med Chem. 2020 Apr 23;63(8):4047-4068. (PMID: 32275432) Angew Chem Int Ed Engl. 2015 Apr 20;54(17):5166-70. (PMID: 25728001) J Biomol Screen. 2015 Feb;20(2):180-9. (PMID: 25266565) Genes Dev. 2000 May 1;14(9):1048-57. (PMID: 10809664) Blood. 2008 Aug 1;112(3):644-51. (PMID: 18487509) J Med Chem. 2017 May 25;60(10):4386-4402. (PMID: 28485934) Curr Opin Hematol. 2008 Jul;15(4):381-90. (PMID: 18536578) Mol Cell. 2003 Dec;12(6):1551-64. (PMID: 14690607) Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32. (PMID: 15572765) J Med Chem. 2017 May 25;60(10):4358-4368. (PMID: 28471657) Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32. (PMID: 20124692) J Biomol Screen. 2003 Feb;8(1):34-8. (PMID: 12854996) J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674. (PMID: 19461840) Clin Cancer Res. 2017 Feb 15;23(4):885-893. (PMID: 27881582) J Med Chem. 2020 Jan 23;63(2):676-695. (PMID: 31895575) Mol Cell. 2008 Feb 15;29(3):384-91. (PMID: 18280243) SLAS Discov. 2021 Sep;26(8):984-994. (PMID: 34330171) Anal Biochem. 2004 Sep 1;332(1):153-9. (PMID: 15301960) J Comput Aided Mol Des. 1997 Nov;11(6):525-37. (PMID: 9491345) Nat Immunol. 2007 Jul;8(7):705-14. (PMID: 17558410) EMBO J. 2000 Aug 15;19(16):4342-50. (PMID: 10944117) J Biomol Screen. 2001 Oct;6(5):275-90. (PMID: 11689128) |
| 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 |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 2045-2322 |
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| DOI: | 10.1038/s41598-022-23264-z |