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- Publisher Website: 10.1021/jacs.0c10324
- Scopus: eid_2-s2.0-85098892464
- PMID: 33306911
- WOS: WOS:000603395100026
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Article: Selective Targeting of AF9 YEATS Domain by Cyclopeptide Inhibitors with Preorganized Conformation
Title | Selective Targeting of AF9 YEATS Domain by Cyclopeptide Inhibitors with Preorganized Conformation |
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Authors | |
Issue Date | 2020 |
Publisher | American Chemical Society. The Journal's web site is located at http://pubs.acs.org/journals/jacsat/index.html |
Citation | Journal of the American Chemical Society, 2020, v. 142, p. 21450-21459 How to Cite? |
Abstract | YEATS domains are newly identified epigenetic “readers” of histone lysine acetylation (Kac) and crotonylation (Kcr). The malfunction of YEATS–Kac/Kcr interactions has been found to be involved in the pathogenesis of human diseases, such as cancer. These discoveries suggest that the YEATS domains are promising novel drug targets. We and others recently reported the development of YEATS domain inhibitors. Although these inhibitors have a general preference toward the AF9 and ENL YEATS domains, selective inhibitors targeting either YEATS domain are challenging to develop as these two proteins share a high structural similarity. In this study, we identified a proximal site outside the acyllysine-binding pocket that can differentiate AF9 YEATS from ENL YEATS. Combinatorial targeting of both the acyllysine pocket and this additional site by conformationally preorganized cyclopeptides enabled the selective inhibition of the AF9 YEATS domain. The most selective inhibitor, JYX-3, showed a 38-fold higher binding affinity toward AF9 YEATS over ENL YEATS. Further investigations indicated that JYX-3 could engage with AF9 in living cells, disrupt the YEATS-dependent chromatin recruitment of AF9, and suppress the transcription of AF9 target genes. |
Persistent Identifier | http://hdl.handle.net/10722/297635 |
ISSN | 2023 Impact Factor: 14.4 2023 SCImago Journal Rankings: 5.489 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | JIANG, Y | - |
dc.contributor.author | CHEN, G | - |
dc.contributor.author | Li, X | - |
dc.contributor.author | LIU, S | - |
dc.contributor.author | Tian, G | - |
dc.contributor.author | LI, Y | - |
dc.contributor.author | Li, X | - |
dc.contributor.author | LI, H | - |
dc.contributor.author | Li, XD | - |
dc.date.accessioned | 2021-03-23T04:19:42Z | - |
dc.date.available | 2021-03-23T04:19:42Z | - |
dc.date.issued | 2020 | - |
dc.identifier.citation | Journal of the American Chemical Society, 2020, v. 142, p. 21450-21459 | - |
dc.identifier.issn | 0002-7863 | - |
dc.identifier.uri | http://hdl.handle.net/10722/297635 | - |
dc.description.abstract | YEATS domains are newly identified epigenetic “readers” of histone lysine acetylation (Kac) and crotonylation (Kcr). The malfunction of YEATS–Kac/Kcr interactions has been found to be involved in the pathogenesis of human diseases, such as cancer. These discoveries suggest that the YEATS domains are promising novel drug targets. We and others recently reported the development of YEATS domain inhibitors. Although these inhibitors have a general preference toward the AF9 and ENL YEATS domains, selective inhibitors targeting either YEATS domain are challenging to develop as these two proteins share a high structural similarity. In this study, we identified a proximal site outside the acyllysine-binding pocket that can differentiate AF9 YEATS from ENL YEATS. Combinatorial targeting of both the acyllysine pocket and this additional site by conformationally preorganized cyclopeptides enabled the selective inhibition of the AF9 YEATS domain. The most selective inhibitor, JYX-3, showed a 38-fold higher binding affinity toward AF9 YEATS over ENL YEATS. Further investigations indicated that JYX-3 could engage with AF9 in living cells, disrupt the YEATS-dependent chromatin recruitment of AF9, and suppress the transcription of AF9 target genes. | - |
dc.language | eng | - |
dc.publisher | American Chemical Society. The Journal's web site is located at http://pubs.acs.org/journals/jacsat/index.html | - |
dc.relation.ispartof | Journal of the American Chemical Society | - |
dc.rights | This document is the Accepted Manuscript version of a Published Work that appeared in final form in [JournalTitle], copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see [insert ACS Articles on Request author-directed link to Published Work, see http://pubs.acs.org/page/policy/articlesonrequest/index.html]. | - |
dc.title | Selective Targeting of AF9 YEATS Domain by Cyclopeptide Inhibitors with Preorganized Conformation | - |
dc.type | Article | - |
dc.identifier.email | Li, X: lixm@hku.hk | - |
dc.identifier.email | Tian, G: tiangf@hku.hk | - |
dc.identifier.email | Li, X: lx418@hku.hk | - |
dc.identifier.email | Li, XD: xiangli@hku.hk | - |
dc.identifier.authority | Li, XD=rp01562 | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1021/jacs.0c10324 | - |
dc.identifier.pmid | 33306911 | - |
dc.identifier.scopus | eid_2-s2.0-85098892464 | - |
dc.identifier.hkuros | 321749 | - |
dc.identifier.volume | 142 | - |
dc.identifier.spage | 21450 | - |
dc.identifier.epage | 21459 | - |
dc.identifier.isi | WOS:000603395100026 | - |
dc.publisher.place | United States | - |