Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy
This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series o...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383520305979 |
| _version_ | 1818639735765073920 |
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| author | Xiaosa Chang Dejuan Sun Danfeng Shi Guan Wang Yanmei Chen Kai Zhang Huidan Tan Jie Liu Bo Liu Liang Ouyang |
| author_facet | Xiaosa Chang Dejuan Sun Danfeng Shi Guan Wang Yanmei Chen Kai Zhang Huidan Tan Jie Liu Bo Liu Liang Ouyang |
| author_sort | Xiaosa Chang |
| collection | DOAJ |
| description | This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragment-based combinatorial screening and activity assays that together led to the chemical optimization. Among these compounds, 19d was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1, respectively. Compound 19d was further shown to efficiently modulate the expression of BRD4 and PARP1. Subsequently, compound 19d was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase. Following pharmacokinetic studies, compound 19d showed its antitumor activity in breast cancer susceptibility gene 1/2 (BRCA1/2) wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight. These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer. |
| first_indexed | 2024-12-16T23:00:06Z |
| format | Article |
| id | doaj.art-a815c10815474d82993eefefa638b7fe |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-12-16T23:00:06Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-a815c10815474d82993eefefa638b7fe2022-12-21T22:12:46ZengElsevierActa Pharmaceutica Sinica B2211-38352021-01-01111156180Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapyXiaosa Chang0Dejuan Sun1Danfeng Shi2Guan Wang3Yanmei Chen4Kai Zhang5Huidan Tan6Jie Liu7Bo Liu8Liang Ouyang9State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, ChinaCorresponding authors. Tel./fax: +86 28 85503817 (Jie Liu), +86 28 85164063 (Bo Liu), +86 28 85503817 (Liang Ouyang).; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, ChinaCorresponding authors. Tel./fax: +86 28 85503817 (Jie Liu), +86 28 85164063 (Bo Liu), +86 28 85503817 (Liang Ouyang).; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, ChinaCorresponding authors. Tel./fax: +86 28 85503817 (Jie Liu), +86 28 85164063 (Bo Liu), +86 28 85503817 (Liang Ouyang).; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, ChinaThis study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragment-based combinatorial screening and activity assays that together led to the chemical optimization. Among these compounds, 19d was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1, respectively. Compound 19d was further shown to efficiently modulate the expression of BRD4 and PARP1. Subsequently, compound 19d was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase. Following pharmacokinetic studies, compound 19d showed its antitumor activity in breast cancer susceptibility gene 1/2 (BRCA1/2) wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight. These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer.http://www.sciencedirect.com/science/article/pii/S2211383520305979BRD4PARP1Dual-target inhibitorSynthetic lethalityQuinazolin-4(3H)-one derivatives |
| spellingShingle | Xiaosa Chang Dejuan Sun Danfeng Shi Guan Wang Yanmei Chen Kai Zhang Huidan Tan Jie Liu Bo Liu Liang Ouyang Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy Acta Pharmaceutica Sinica B BRD4 PARP1 Dual-target inhibitor Synthetic lethality Quinazolin-4(3H)-one derivatives |
| title | Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy |
| title_full | Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy |
| title_fullStr | Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy |
| title_full_unstemmed | Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy |
| title_short | Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy |
| title_sort | design synthesis and biological evaluation of quinazolin 4 3h one derivatives co targeting poly adp ribose polymerase 1 and bromodomain containing protein 4 for breast cancer therapy |
| topic | BRD4 PARP1 Dual-target inhibitor Synthetic lethality Quinazolin-4(3H)-one derivatives |
| url | http://www.sciencedirect.com/science/article/pii/S2211383520305979 |
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