دورية أكاديمية
Fragment-based Scaffold Hopping: Identification of Potent, Selective, and Highly Soluble Bromo and Extra Terminal Domain (BET) Second Bromodomain (BD2) Inhibitors.
| العنوان: | Fragment-based Scaffold Hopping: Identification of Potent, Selective, and Highly Soluble Bromo and Extra Terminal Domain (BET) Second Bromodomain (BD2) Inhibitors. |
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| المؤلفون: | Seal JT, Atkinson SJ, Bamborough P, Bassil A, Chung CW, Foley J; Cancer Epigenetics Research Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Gordon L, Grandi P; IVIVT Cellzome, Platform Technology and Science, GlaxoSmithKline, Meyerhofstr. 1, 69117 Heidelberg, Germany., Gray JRJ, Harrison LA, Kruger RG; Cancer Epigenetics Research Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Matteo JJ; Cancer Epigenetics Research Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., McCabe MT; Cancer Epigenetics Research Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Messenger C, Mitchell D, Phillipou A, Preston A, Prinjha RK, Rianjongdee F, Rioja I, Taylor S, Wall ID, Watson RJ, Woolven JM, Wyce A; Cancer Epigenetics Research Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Zhang XP; Cancer Epigenetics Research Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Demont EH |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2021 Aug 12; Vol. 64 (15), pp. 10772-10805. Date of Electronic Publication: 2021 Jul 13. |
| نوع المنشور: | Journal Article |
| 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: | Furans/*pharmacology , Proteins/*antagonists & inhibitors , Pyrazoles/*pharmacology, Dose-Response Relationship, Drug ; Furans/chemistry ; Humans ; Molecular Structure ; Proteins/metabolism ; Pyrazoles/chemistry ; Structure-Activity Relationship |
| مستخلص: | The profound efficacy of pan-BET inhibitors is well documented, but these epigenetic agents have shown pharmacology-driven toxicity in oncology clinical trials. The opportunity to identify inhibitors with an improved safety profile by selective targeting of a subset of the eight bromodomains of the BET family has triggered extensive medicinal chemistry efforts. In this article, we disclose the identification of potent and selective drug-like pan-BD2 inhibitors such as pyrazole 23 (GSK809) and furan 24 (GSK743) that were derived from the pyrrole fragment 6 . We transpose the key learnings from a previous pyridone series (GSK620 2 as a representative example) to this novel class of inhibitors, which are characterized by significantly improved solubility relative to our previous research. |
| المشرفين على المادة: | 0 (Furans) 0 (Proteins) 0 (Pyrazoles) 0 (bromodomain and extra-terminal domain protein, human) 3QD5KJZ7ZJ (pyrazole) |
| تواريخ الأحداث: | Date Created: 20210713 Date Completed: 20211020 Latest Revision: 20211020 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1021/acs.jmedchem.1c00365 |
| PMID: | 34255512 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.1c00365 |