Crystal structure of [1,2,4] triazolo[4,3- b ]pyridazine derivatives as BRD4 bromodomain inhibitors and structure–activity relationship study
Abstract BRD4 contains two tandem bromodomains (BD1 and BD2) that recognize acetylated lysine for epigenetic reading, and these bromodomains are promising therapeutic targets for treating various diseases, including cancers. BRD4 is a well-studied target, and many chemical scaffolds for inhibitors h...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-37527-w |
| _version_ | 1797784622332903424 |
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| author | Jung-Hoon Kim Navin Pandit Miyoun Yoo Tae Hyun Park Ji U Choi Chi Hoon Park Kwan-Young Jung Byung Il Lee |
| author_facet | Jung-Hoon Kim Navin Pandit Miyoun Yoo Tae Hyun Park Ji U Choi Chi Hoon Park Kwan-Young Jung Byung Il Lee |
| author_sort | Jung-Hoon Kim |
| collection | DOAJ |
| description | Abstract BRD4 contains two tandem bromodomains (BD1 and BD2) that recognize acetylated lysine for epigenetic reading, and these bromodomains are promising therapeutic targets for treating various diseases, including cancers. BRD4 is a well-studied target, and many chemical scaffolds for inhibitors have been developed. Research on the development of BRD4 inhibitors against various diseases is actively being conducted. Herein, we propose a series of [1,2,4]triazolo[4,3-b]pyridazine derivatives as bromodomain inhibitors with micromolar IC50 values. We characterized the binding modes by determining the crystal structures of BD1 in complex with four selected inhibitors. Compounds containing [1,2,4] triazolo[4,3-b]pyridazine derivatives offer promising starting molecules for designing potent BRD4 BD inhibitors. |
| first_indexed | 2024-03-13T00:42:31Z |
| format | Article |
| id | doaj.art-623dd08333ab478685ee7e9f421794fd |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-13T00:42:31Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-623dd08333ab478685ee7e9f421794fd2023-07-09T11:12:41ZengNature PortfolioScientific Reports2045-23222023-07-0113111210.1038/s41598-023-37527-wCrystal structure of [1,2,4] triazolo[4,3- b ]pyridazine derivatives as BRD4 bromodomain inhibitors and structure–activity relationship studyJung-Hoon Kim0Navin Pandit1Miyoun Yoo2Tae Hyun Park3Ji U Choi4Chi Hoon Park5Kwan-Young Jung6Byung Il Lee7Research Institute, National Cancer CenterDepartment of Medicinal Chemistry and Pharmacology, University of Science and TechnologyTherapeutics and Biotechnology Division, Korea Research Institute of Chemical TechnologyDepartment of Anesthesiology, Weill Cornell Medical CollegeDepartment of Medicinal Chemistry and Pharmacology, University of Science and TechnologyDepartment of Medicinal Chemistry and Pharmacology, University of Science and TechnologyDepartment of Medicinal Chemistry and Pharmacology, University of Science and TechnologyResearch Institute, National Cancer CenterAbstract BRD4 contains two tandem bromodomains (BD1 and BD2) that recognize acetylated lysine for epigenetic reading, and these bromodomains are promising therapeutic targets for treating various diseases, including cancers. BRD4 is a well-studied target, and many chemical scaffolds for inhibitors have been developed. Research on the development of BRD4 inhibitors against various diseases is actively being conducted. Herein, we propose a series of [1,2,4]triazolo[4,3-b]pyridazine derivatives as bromodomain inhibitors with micromolar IC50 values. We characterized the binding modes by determining the crystal structures of BD1 in complex with four selected inhibitors. Compounds containing [1,2,4] triazolo[4,3-b]pyridazine derivatives offer promising starting molecules for designing potent BRD4 BD inhibitors.https://doi.org/10.1038/s41598-023-37527-w |
| spellingShingle | Jung-Hoon Kim Navin Pandit Miyoun Yoo Tae Hyun Park Ji U Choi Chi Hoon Park Kwan-Young Jung Byung Il Lee Crystal structure of [1,2,4] triazolo[4,3- b ]pyridazine derivatives as BRD4 bromodomain inhibitors and structure–activity relationship study Scientific Reports |
| title | Crystal structure of [1,2,4] triazolo[4,3- b ]pyridazine derivatives as BRD4 bromodomain inhibitors and structure–activity relationship study |
| title_full | Crystal structure of [1,2,4] triazolo[4,3- b ]pyridazine derivatives as BRD4 bromodomain inhibitors and structure–activity relationship study |
| title_fullStr | Crystal structure of [1,2,4] triazolo[4,3- b ]pyridazine derivatives as BRD4 bromodomain inhibitors and structure–activity relationship study |
| title_full_unstemmed | Crystal structure of [1,2,4] triazolo[4,3- b ]pyridazine derivatives as BRD4 bromodomain inhibitors and structure–activity relationship study |
| title_short | Crystal structure of [1,2,4] triazolo[4,3- b ]pyridazine derivatives as BRD4 bromodomain inhibitors and structure–activity relationship study |
| title_sort | crystal structure of 1 2 4 triazolo 4 3 b pyridazine derivatives as brd4 bromodomain inhibitors and structure activity relationship study |
| url | https://doi.org/10.1038/s41598-023-37527-w |
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