دورية أكاديمية
Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders.
| العنوان: | Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders. |
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| المؤلفون: | Bellenie BR, Cheung KJ, Varela A, Pierrat OA, Collie GW, Box GM, Bright MD, Gowan S, Hayes A, Rodrigues MJ, Shetty KN, Carter M, Davis OA, Henley AT, Innocenti P, Johnson LD, Liu M, de Klerk S, Le Bihan YV, Lloyd MG, McAndrew PC, Shehu E, Talbot R, Woodward HL, Burke R, Kirkin V, van Montfort RLM, Raynaud FI, Rossanese OW, Hoelder S |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2020 Apr 23; Vol. 63 (8), pp. 4047-4068. Date of Electronic Publication: 2020 Apr 10. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | Benzimidazoles/*administration & dosage , Benzimidazoles/*chemistry , Drug Delivery Systems/*methods , Drug Discovery/*methods , Proto-Oncogene Proteins c-bcl-6/*antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-6/*metabolism, Animals ; Cell Line, Tumor ; Female ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, SCID ; Microsomes, Liver/drug effects ; Microsomes, Liver/metabolism ; Protein Structure, Tertiary ; Rats ; Rats, Sprague-Dawley ; Xenograft Model Antitumor Assays/methods |
| مستخلص: | Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3 R ,5 S )-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2 H -benzo[ d ]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing. |
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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 (BCL6 protein, human) 0 (Benzimidazoles) 0 (Proto-Oncogene Proteins c-bcl-6) 20662-53-7 (benzimidazolone) |
| تواريخ الأحداث: | Date Created: 20200411 Date Completed: 20200924 Latest Revision: 20240210 |
| رمز التحديث: | 20240210 |
| مُعرف محوري في PubMed: | PMC7184563 |
| DOI: | 10.1021/acs.jmedchem.9b02076 |
| PMID: | 32275432 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.9b02076 |