دورية أكاديمية
Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors.
| العنوان: | Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors. |
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| المؤلفون: | Davis OA; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., Cheung KJ; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., Brennan A; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., Lloyd MG; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., Rodrigues MJ; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K..; Division of Structural Biology, The Institute of Cancer Research, London SM2 5NG, U.K.., Pierrat OA; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., Collie GW; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K..; Division of Structural Biology, The Institute of Cancer Research, London SM2 5NG, U.K.., Le Bihan YV; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K..; Division of Structural Biology, The Institute of Cancer Research, London SM2 5NG, U.K.., Huckvale R; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., Harnden AC; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., Varela A; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., Bright MD; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., Eve P; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., Hayes A; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., Henley AT; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., Carter MD; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., McAndrew PC; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., Talbot R; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., Burke R; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., van Montfort RLM; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K..; Division of Structural Biology, The Institute of Cancer Research, London SM2 5NG, U.K.., Raynaud FI; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., Rossanese OW; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., Meniconi M; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., Bellenie BR; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.., Hoelder S; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2022 Jun 23; Vol. 65 (12), pp. 8169-8190. Date of Electronic Publication: 2022 Jun 03. |
| 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: | BTB-POZ Domain*, Protein Binding ; Proto-Oncogene Proteins c-bcl-6 |
| مستخلص: | To identify new chemical series with enhanced binding affinity to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket adjacent to Val18. With no opportunities for strong polar interactions, we focused on attaining close shape complementarity by ring fusion onto our quinolinone lead series. Following exploration of different sized rings, we identified a conformationally restricted core which optimally filled the available space, leading to potent BCL6 inhibitors. Through X-ray structure-guided design, combined with efficient synthetic chemistry to make the resulting novel core structures, a >300-fold improvement in activity was obtained by the addition of seven heavy atoms. |
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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) |
| تواريخ الأحداث: | Date Created: 20220603 Date Completed: 20220624 Latest Revision: 20240210 |
| رمز التحديث: | 20240210 |
| مُعرف محوري في PubMed: | PMC9234963 |
| DOI: | 10.1021/acs.jmedchem.1c02174 |
| PMID: | 35657291 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.1c02174 |