Fragment-Based Discovery of AF9 YEATS Domain Inhibitors
YEATS (YAF9, ENL, AF9, TAF14, SAS5) family proteins recognize acylated histones and in turn regulate chromatin structure, gene transcription, and stress signaling. The chromosomal translocations of ENL and mixed lineage leukemia are considered oncogenic drivers in acute myeloid leukemia and acute ly...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/7/3893 |
| _version_ | 1797438965781889024 |
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| author | Yaqian Liu Ruoxing Jin Hui Lu Kangjie Bian Rui Wang Lei Wang Rui Gao Jiahai Zhang Jihui Wu Xuebiao Yao Xing Liu Dan Liu Xisheng Wang Zhiyong Zhang Ke Ruan |
| author_facet | Yaqian Liu Ruoxing Jin Hui Lu Kangjie Bian Rui Wang Lei Wang Rui Gao Jiahai Zhang Jihui Wu Xuebiao Yao Xing Liu Dan Liu Xisheng Wang Zhiyong Zhang Ke Ruan |
| author_sort | Yaqian Liu |
| collection | DOAJ |
| description | YEATS (YAF9, ENL, AF9, TAF14, SAS5) family proteins recognize acylated histones and in turn regulate chromatin structure, gene transcription, and stress signaling. The chromosomal translocations of ENL and mixed lineage leukemia are considered oncogenic drivers in acute myeloid leukemia and acute lymphoid leukemia. However, known ENL YEATS domain inhibitors have failed to suppress the proliferation of 60 tested cancer cell lines. Herein, we identified four hits from the NMR fragment-based screening against the AF9 YEATS domain. Ten inhibitors of new chemotypes were then designed and synthesized guided by two complex structures and affinity assays. The complex structures revealed that these inhibitors formed an extra hydrogen bond to AF9, with respect to known ENL inhibitors. Furthermore, these inhibitors demonstrated antiproliferation activities in AF9-sensitive HGC-27 cells, which recapitulated the phenotype of the CRISPR studies against AF9. Our work will provide the basis for further structured-based optimization and reignite the campaign for potent AF9 YEATS inhibitors as a precise treatment for AF9-sensitive cancers. |
| first_indexed | 2024-03-09T11:45:55Z |
| format | Article |
| id | doaj.art-d443feb262be4ae3be665a5ae9160212 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T11:45:55Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d443feb262be4ae3be665a5ae91602122023-11-30T23:23:40ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-03-01237389310.3390/ijms23073893Fragment-Based Discovery of AF9 YEATS Domain InhibitorsYaqian Liu0Ruoxing Jin1Hui Lu2Kangjie Bian3Rui Wang4Lei Wang5Rui Gao6Jiahai Zhang7Jihui Wu8Xuebiao Yao9Xing Liu10Dan Liu11Xisheng Wang12Zhiyong Zhang13Ke Ruan14Ministry of Education Key Laboratory for Membraneless Organelles & Cellular Dynamics, Biomedical Sciences and Health Laboratory of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaDepartment of Chemistry, University of Science and Technology of China, Hefei 230026, ChinaMinistry of Education Key Laboratory for Membraneless Organelles & Cellular Dynamics, Biomedical Sciences and Health Laboratory of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaDepartment of Chemistry, University of Science and Technology of China, Hefei 230026, ChinaDepartment of Chemistry, University of Science and Technology of China, Hefei 230026, ChinaMinistry of Education Key Laboratory for Membraneless Organelles & Cellular Dynamics, Biomedical Sciences and Health Laboratory of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaMinistry of Education Key Laboratory for Membraneless Organelles & Cellular Dynamics, Biomedical Sciences and Health Laboratory of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaMinistry of Education Key Laboratory for Membraneless Organelles & Cellular Dynamics, Biomedical Sciences and Health Laboratory of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaMinistry of Education Key Laboratory for Membraneless Organelles & Cellular Dynamics, Biomedical Sciences and Health Laboratory of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaMinistry of Education Key Laboratory for Membraneless Organelles & Cellular Dynamics, Biomedical Sciences and Health Laboratory of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaMinistry of Education Key Laboratory for Membraneless Organelles & Cellular Dynamics, Biomedical Sciences and Health Laboratory of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaMinistry of Education Key Laboratory for Membraneless Organelles & Cellular Dynamics, Biomedical Sciences and Health Laboratory of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaDepartment of Chemistry, University of Science and Technology of China, Hefei 230026, ChinaMinistry of Education Key Laboratory for Membraneless Organelles & Cellular Dynamics, Biomedical Sciences and Health Laboratory of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaMinistry of Education Key Laboratory for Membraneless Organelles & Cellular Dynamics, Biomedical Sciences and Health Laboratory of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaYEATS (YAF9, ENL, AF9, TAF14, SAS5) family proteins recognize acylated histones and in turn regulate chromatin structure, gene transcription, and stress signaling. The chromosomal translocations of ENL and mixed lineage leukemia are considered oncogenic drivers in acute myeloid leukemia and acute lymphoid leukemia. However, known ENL YEATS domain inhibitors have failed to suppress the proliferation of 60 tested cancer cell lines. Herein, we identified four hits from the NMR fragment-based screening against the AF9 YEATS domain. Ten inhibitors of new chemotypes were then designed and synthesized guided by two complex structures and affinity assays. The complex structures revealed that these inhibitors formed an extra hydrogen bond to AF9, with respect to known ENL inhibitors. Furthermore, these inhibitors demonstrated antiproliferation activities in AF9-sensitive HGC-27 cells, which recapitulated the phenotype of the CRISPR studies against AF9. Our work will provide the basis for further structured-based optimization and reignite the campaign for potent AF9 YEATS inhibitors as a precise treatment for AF9-sensitive cancers.https://www.mdpi.com/1422-0067/23/7/3893fragment-based lead discoverypost-translational modificationhistone acylationYEATS domainNMR fragment-based screening |
| spellingShingle | Yaqian Liu Ruoxing Jin Hui Lu Kangjie Bian Rui Wang Lei Wang Rui Gao Jiahai Zhang Jihui Wu Xuebiao Yao Xing Liu Dan Liu Xisheng Wang Zhiyong Zhang Ke Ruan Fragment-Based Discovery of AF9 YEATS Domain Inhibitors International Journal of Molecular Sciences fragment-based lead discovery post-translational modification histone acylation YEATS domain NMR fragment-based screening |
| title | Fragment-Based Discovery of AF9 YEATS Domain Inhibitors |
| title_full | Fragment-Based Discovery of AF9 YEATS Domain Inhibitors |
| title_fullStr | Fragment-Based Discovery of AF9 YEATS Domain Inhibitors |
| title_full_unstemmed | Fragment-Based Discovery of AF9 YEATS Domain Inhibitors |
| title_short | Fragment-Based Discovery of AF9 YEATS Domain Inhibitors |
| title_sort | fragment based discovery of af9 yeats domain inhibitors |
| topic | fragment-based lead discovery post-translational modification histone acylation YEATS domain NMR fragment-based screening |
| url | https://www.mdpi.com/1422-0067/23/7/3893 |
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