Optimization of a Protein-Targeted Medicine into an RNA-Specific Small Molecule
Protein-targeted small molecule medicines often bind RNAs and affect RNA-mediated pathways in cells. Historically, small molecule engagement and modulation of RNA have not been considered in medicine development; however, RNA should be considered both a potential on- and off-target. Kinase inhibitors have emecrged as common RNA binders with dovitinib, a classic receptor tyrosine kinase (RTK) inhibitor, inhibiting RTKs and the biogenesis of oncogenic microRNA-21 through direct engagement. In this study, we use knowledge of the molecular recognition of both protein and RNA targets by dovitinib to design molecules that specifically inhibit the RNA target but lack activity against canonical protein targets in cells. As it is now becoming apparent that RNA can be both an on- and off-target for small molecule medicines, this study lays a foundation to use design principles to maximize desired compound activity while minimizing off-target effects.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:18 |
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| Enthalten in: |
ACS chemical biology - 18(2023), 11 vom: 17. Nov., Seite 2336-2342 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Meyer, Samantha M [VerfasserIn] |
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| Links: |
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| Themen: |
EC 2.7.10.1 |
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| Anmerkungen: |
Date Completed 20.11.2023 Date Revised 01.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acschembio.3c00476 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Protein-targeted small molecule medicines often bind RNAs and affect RNA-mediated pathways in cells. Historically, small molecule engagement and modulation of RNA have not been considered in medicine development; however, RNA should be considered both a potential on- and off-target. Kinase inhibitors have emecrged as common RNA binders with dovitinib, a classic receptor tyrosine kinase (RTK) inhibitor, inhibiting RTKs and the biogenesis of oncogenic microRNA-21 through direct engagement. In this study, we use knowledge of the molecular recognition of both protein and RNA targets by dovitinib to design molecules that specifically inhibit the RNA target but lack activity against canonical protein targets in cells. As it is now becoming apparent that RNA can be both an on- and off-target for small molecule medicines, this study lays a foundation to use design principles to maximize desired compound activity while minimizing off-target effects | ||
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| 700 | 1 | |a Baisden, Jared T |e verfasserin |4 aut | |
| 700 | 1 | |a Grefe, Maison |e verfasserin |4 aut | |
| 700 | 1 | |a Disney, Matthew D |e verfasserin |4 aut | |
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