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Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3
SMYD3 is a histone methyltransferase that regulates gene transcription, and its overexpression is associated with multiple human cancers. A novel class of tetrahydroacridine compounds which inhibit SMYD3 through a covalent mechanism of action is identified. Optimization of these irreversible inhibit...
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| Published in: | ACS medicinal chemistry letters 2019-06, Vol.10 (6), p.978-984 |
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| creator | Huang, Chuhui Liew, Si Si Lin, Grace R Poulsen, Anders Ang, Melgious J. Y Chia, Brian C. S Chew, Sin Yin Kwek, Zekui P Wee, John L. K Ong, Esther H Retna, Priya Baburajendran, Nithya Li, Rong Yu, Weixuan Koh-Stenta, Xiaoying Ngo, Anna Manesh, Sravanthy Fulwood, Justina Ke, Zhiyuan Chung, Hwa Hwa Sepramaniam, Sugunavathi Chew, Xin Hui Dinie, Nurul Lee, May Ann Chew, Yun Shan Low, Choon Bing Pendharkar, Vishal Manoharan, Vithya Vuddagiri, Susmitha Sangthongpitag, Kanda Joy, Joma Matter, Alex Hill, Jeffrey Keller, Thomas H Foo, Klement |
| description | SMYD3 is a histone methyltransferase that regulates gene transcription, and its overexpression is associated with multiple human cancers. A novel class of tetrahydroacridine compounds which inhibit SMYD3 through a covalent mechanism of action is identified. Optimization of these irreversible inhibitors resulted in the discovery of 4-chloroquinolines, a new class of covalent warheads. Tool compound 29 exhibits high potency by inhibiting SMYD3′s enzymatic activity and showing antiproliferative activity against HepG2 in 3D cell culture. Our findings suggest that covalent inhibition of SMYD3 may have an impact on SMYD3 biology by affecting expression levels, and this warrants further exploration. |
| doi_str_mv | 10.1021/acsmedchemlett.9b00170 |
| format | article |
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Tool compound 29 exhibits high potency by inhibiting SMYD3′s enzymatic activity and showing antiproliferative activity against HepG2 in 3D cell culture. 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Lett</addtitle><date>2019-06-13</date><risdate>2019</risdate><volume>10</volume><issue>6</issue><spage>978</spage><epage>984</epage><pages>978-984</pages><issn>1948-5875</issn><eissn>1948-5875</eissn><abstract>SMYD3 is a histone methyltransferase that regulates gene transcription, and its overexpression is associated with multiple human cancers. A novel class of tetrahydroacridine compounds which inhibit SMYD3 through a covalent mechanism of action is identified. Optimization of these irreversible inhibitors resulted in the discovery of 4-chloroquinolines, a new class of covalent warheads. Tool compound 29 exhibits high potency by inhibiting SMYD3′s enzymatic activity and showing antiproliferative activity against HepG2 in 3D cell culture. 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| fulltext | fulltext |
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| ispartof | ACS medicinal chemistry letters, 2019-06, Vol.10 (6), p.978-984 |
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| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6580565 |
| source | American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list); PubMed Central |
| subjects | Letter |
| title | Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3 |
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