Discovery of Allosteric Inhibitors Targeting the Spliceosomal RNA Helicase Brr2
| Autor: | Michael G. Klein, Masanori Miwa, Daisuke Morishita, Kazuko Yonemori, Masahiro Ito, Toshio Tanaka, Atsushi Nakanishi, Richard Tjhen, Ling Qin, Hironobu Maezaki, Tomohiro Kawamoto, Takeshi Yamamoto, Satoshi Endo, Misa Iwatani-Yoshihara |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Spliceosome Subfamily ATPase Allosteric regulation Crystallography X-Ray 03 medical and health sciences 0302 clinical medicine Allosteric Regulation Drug Discovery Humans Enzyme Inhibitors biology Chemistry Helicase RNA RNA Helicase A Molecular biology Molecular Docking Simulation 030104 developmental biology Pyrimidines Biochemistry 030220 oncology & carcinogenesis Drug Design biology.protein Spliceosomes Molecular Medicine Molecular probe RNA Helicases |
| Zdroj: | Journal of medicinal chemistry. 60(13) |
| ISSN: | 1520-4804 |
| Popis: | Brr2 is an RNA helicase belonging to the Ski2-like subfamily and an essential component of spliceosome. Brr2 catalyzes an ATP-dependent unwinding of the U4/U6 RNA duplex, which is a critical step for spliceosomal activation. An HTS campaign using an RNA-dependent ATPase assay and initial SAR study identified two different Brr2 inhibitors, 3 and 12. Cocrystal structures revealed 3 binds to an unexpected allosteric site between the C-terminal and the N-terminal helicase cassettes, while 12 binds an RNA-binding site inside the N-terminal cassette. Selectivity profiling indicated the allosteric inhibitor 3 is more Brr2-selective than the RNA site binder 12. Chemical optimization of 3 using SBDD culminated in the discovery of the potent and selective Brr2 inhibitor 9 with helicase inhibitory activity. Our findings demonstrate an effective strategy to explore selective inhibitors for helicases, and 9 could be a promising starting point for exploring molecular probes to elucidate biological functions and the therapeutic relevance of Brr2. |
| Databáze: | OpenAIRE |
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