Discovery of the natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 bromodomain 2 inhibitor
Bromodomain-containing protein 4 (BRD4) binds acetylated lysine residues on the N-terminal tails of histones through two bromodomains (BD1 and BD2) to regulate gene transcription. Inhibiting one or both of bromodomains resulted in different phenotypes, suggesting BD1 and BD2 may have different funct...
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doaj-00898fc474ab400aa77e14f3c7f409b32021-04-21T16:14:24ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742021-01-0136190391310.1080/14756366.2021.19066631906663Discovery of the natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 bromodomain 2 inhibitorJiao Li0Wei Zou1Koukou Yu2Bing Liu3Weifeng Liang4Lisha Wang5Yin Lu6Zequn Jiang7Aiyun Wang8Jiapeng Zhu9School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese MedicineSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineDepartment of Medicinal Chemistry, PharmaBlock Sciences (Nanjing), IncJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese MedicineSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese MedicineSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineBromodomain-containing protein 4 (BRD4) binds acetylated lysine residues on the N-terminal tails of histones through two bromodomains (BD1 and BD2) to regulate gene transcription. Inhibiting one or both of bromodomains resulted in different phenotypes, suggesting BD1 and BD2 may have different functions. Here we report the characterisation of a natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 inhibitor. The compound is 100-fold more selective for BRD4-BD2 (IC50 = 204 nM) than BRD4-BD1 (IC50=17.9 µM). Co-crystal structures show 3',4',7,8-tetrahydroxyflavone binds to the acetylated lysine binding pocket of BRD4-BD1 or BRD4-BD2, but establishes more interactions with BRD4-BD2 than BRD4-BD1. Our data suggest 3',4',7,8-tetrahydroxyflavone as a potent selective inhibitor of BRD4-BD2 with a novel chemical scaffold. Given its distinct chemical structure from current BRD4 inhibitors, this compound may open the door for a novel class of anti-BRD4 inhibitors by serving as a lead compound.http://dx.doi.org/10.1080/14756366.2021.1906663bromodomain-containing protein 4natural product3',4',7,8-tetrahydroxyflavoneinhibitorco-crystal structure |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jiao Li Wei Zou Koukou Yu Bing Liu Weifeng Liang Lisha Wang Yin Lu Zequn Jiang Aiyun Wang Jiapeng Zhu |
spellingShingle |
Jiao Li Wei Zou Koukou Yu Bing Liu Weifeng Liang Lisha Wang Yin Lu Zequn Jiang Aiyun Wang Jiapeng Zhu Discovery of the natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 bromodomain 2 inhibitor Journal of Enzyme Inhibition and Medicinal Chemistry bromodomain-containing protein 4 natural product 3',4',7,8-tetrahydroxyflavone inhibitor co-crystal structure |
author_facet |
Jiao Li Wei Zou Koukou Yu Bing Liu Weifeng Liang Lisha Wang Yin Lu Zequn Jiang Aiyun Wang Jiapeng Zhu |
author_sort |
Jiao Li |
title |
Discovery of the natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 bromodomain 2 inhibitor |
title_short |
Discovery of the natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 bromodomain 2 inhibitor |
title_full |
Discovery of the natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 bromodomain 2 inhibitor |
title_fullStr |
Discovery of the natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 bromodomain 2 inhibitor |
title_full_unstemmed |
Discovery of the natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 bromodomain 2 inhibitor |
title_sort |
discovery of the natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective brd4 bromodomain 2 inhibitor |
publisher |
Taylor & Francis Group |
series |
Journal of Enzyme Inhibition and Medicinal Chemistry |
issn |
1475-6366 1475-6374 |
publishDate |
2021-01-01 |
description |
Bromodomain-containing protein 4 (BRD4) binds acetylated lysine residues on the N-terminal tails of histones through two bromodomains (BD1 and BD2) to regulate gene transcription. Inhibiting one or both of bromodomains resulted in different phenotypes, suggesting BD1 and BD2 may have different functions. Here we report the characterisation of a natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 inhibitor. The compound is 100-fold more selective for BRD4-BD2 (IC50 = 204 nM) than BRD4-BD1 (IC50=17.9 µM). Co-crystal structures show 3',4',7,8-tetrahydroxyflavone binds to the acetylated lysine binding pocket of BRD4-BD1 or BRD4-BD2, but establishes more interactions with BRD4-BD2 than BRD4-BD1. Our data suggest 3',4',7,8-tetrahydroxyflavone as a potent selective inhibitor of BRD4-BD2 with a novel chemical scaffold. Given its distinct chemical structure from current BRD4 inhibitors, this compound may open the door for a novel class of anti-BRD4 inhibitors by serving as a lead compound. |
topic |
bromodomain-containing protein 4 natural product 3',4',7,8-tetrahydroxyflavone inhibitor co-crystal structure |
url |
http://dx.doi.org/10.1080/14756366.2021.1906663 |
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