Exploiting ELIOT for Scaffold-Repurposing Opportunities: TRIM33 a Possible Novel E3 Ligase to Expand the Toolbox for PROTAC Design
The field of targeted protein degradation, through the control of the ubiquitin–proteasome system (UPS), is progressing considerably; to exploit this new therapeutic modality, the proteolysis targeting chimera (PROTAC) technology was born. The opportunity to use PROTACs engaging of new E3 ligases th...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/22/14218 |
| _version_ | 1797465091966238720 |
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| author | Tommaso Palomba Giusy Tassone Carmine Vacca Matteo Bartalucci Aurora Valeri Cecilia Pozzi Simon Cross Lydia Siragusa Jenny Desantis |
| author_facet | Tommaso Palomba Giusy Tassone Carmine Vacca Matteo Bartalucci Aurora Valeri Cecilia Pozzi Simon Cross Lydia Siragusa Jenny Desantis |
| author_sort | Tommaso Palomba |
| collection | DOAJ |
| description | The field of targeted protein degradation, through the control of the ubiquitin–proteasome system (UPS), is progressing considerably; to exploit this new therapeutic modality, the proteolysis targeting chimera (PROTAC) technology was born. The opportunity to use PROTACs engaging of new E3 ligases that can hijack and control the UPS system could greatly extend the applicability of degrading molecules. To this end, here we show a potential application of the ELIOT (E3 LIgase pocketOme navigaTor) platform, previously published by this group, for a scaffold-repurposing strategy to identify new ligands for a novel E3 ligase, such as TRIM33. Starting from ELIOT, a case study of the cross-relationship using GRID Molecular Interaction Field (MIF) similarities between TRIM24 and TRIM33 binding sites was selected. Based on the assumption that similar pockets could bind similar ligands and considering that TRIM24 has 12 known co-crystalised ligands, we applied a scaffold-repurposing strategy for the identification of TRIM33 ligands exploiting the scaffold of TRIM24 ligands. We performed a deeper computational analysis to identify pocket similarities and differences, followed by docking and water analysis; selected ligands were synthesised and subsequently tested against TRIM33 via HTRF binding assay, and we obtained the first-ever X-ray crystallographic complexes of TRIM33α with three of the selected compounds. |
| first_indexed | 2024-03-09T18:16:29Z |
| format | Article |
| id | doaj.art-3746b5fdb19a430aa4718c71306cfa7d |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T18:16:29Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-3746b5fdb19a430aa4718c71306cfa7d2023-11-24T08:40:29ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123221421810.3390/ijms232214218Exploiting ELIOT for Scaffold-Repurposing Opportunities: TRIM33 a Possible Novel E3 Ligase to Expand the Toolbox for PROTAC DesignTommaso Palomba0Giusy Tassone1Carmine Vacca2Matteo Bartalucci3Aurora Valeri4Cecilia Pozzi5Simon Cross6Lydia Siragusa7Jenny Desantis8Department of Chemistry, Biology and Biotechnology, University of Perugia, Via Elce di Sotto, 8, 06132 Perugia, ItalyDepartment of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 2, 53100 Siena, ItalyDepartment of Chemistry, Biology and Biotechnology, University of Perugia, Via Elce di Sotto, 8, 06132 Perugia, ItalyDepartment of Chemistry, Biology and Biotechnology, University of Perugia, Via Elce di Sotto, 8, 06132 Perugia, ItalyMolecular Horizon srl, Via Montelino, 20, 06084 Bettona, ItalyDepartment of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 2, 53100 Siena, ItalyKinetic Business Centre, Molecular Discovery Ltd., Theobald Street, Elstree, Borehamwood, Hertfordshire WD6 4PJ, UKMolecular Horizon srl, Via Montelino, 20, 06084 Bettona, ItalyDepartment of Chemistry, Biology and Biotechnology, University of Perugia, Via Elce di Sotto, 8, 06132 Perugia, ItalyThe field of targeted protein degradation, through the control of the ubiquitin–proteasome system (UPS), is progressing considerably; to exploit this new therapeutic modality, the proteolysis targeting chimera (PROTAC) technology was born. The opportunity to use PROTACs engaging of new E3 ligases that can hijack and control the UPS system could greatly extend the applicability of degrading molecules. To this end, here we show a potential application of the ELIOT (E3 LIgase pocketOme navigaTor) platform, previously published by this group, for a scaffold-repurposing strategy to identify new ligands for a novel E3 ligase, such as TRIM33. Starting from ELIOT, a case study of the cross-relationship using GRID Molecular Interaction Field (MIF) similarities between TRIM24 and TRIM33 binding sites was selected. Based on the assumption that similar pockets could bind similar ligands and considering that TRIM24 has 12 known co-crystalised ligands, we applied a scaffold-repurposing strategy for the identification of TRIM33 ligands exploiting the scaffold of TRIM24 ligands. We performed a deeper computational analysis to identify pocket similarities and differences, followed by docking and water analysis; selected ligands were synthesised and subsequently tested against TRIM33 via HTRF binding assay, and we obtained the first-ever X-ray crystallographic complexes of TRIM33α with three of the selected compounds.https://www.mdpi.com/1422-0067/23/22/14218PROTACE3 ligasescaffold-repurposingBRDTRIM33TRIM24 |
| spellingShingle | Tommaso Palomba Giusy Tassone Carmine Vacca Matteo Bartalucci Aurora Valeri Cecilia Pozzi Simon Cross Lydia Siragusa Jenny Desantis Exploiting ELIOT for Scaffold-Repurposing Opportunities: TRIM33 a Possible Novel E3 Ligase to Expand the Toolbox for PROTAC Design International Journal of Molecular Sciences PROTAC E3 ligase scaffold-repurposing BRD TRIM33 TRIM24 |
| title | Exploiting ELIOT for Scaffold-Repurposing Opportunities: TRIM33 a Possible Novel E3 Ligase to Expand the Toolbox for PROTAC Design |
| title_full | Exploiting ELIOT for Scaffold-Repurposing Opportunities: TRIM33 a Possible Novel E3 Ligase to Expand the Toolbox for PROTAC Design |
| title_fullStr | Exploiting ELIOT for Scaffold-Repurposing Opportunities: TRIM33 a Possible Novel E3 Ligase to Expand the Toolbox for PROTAC Design |
| title_full_unstemmed | Exploiting ELIOT for Scaffold-Repurposing Opportunities: TRIM33 a Possible Novel E3 Ligase to Expand the Toolbox for PROTAC Design |
| title_short | Exploiting ELIOT for Scaffold-Repurposing Opportunities: TRIM33 a Possible Novel E3 Ligase to Expand the Toolbox for PROTAC Design |
| title_sort | exploiting eliot for scaffold repurposing opportunities trim33 a possible novel e3 ligase to expand the toolbox for protac design |
| topic | PROTAC E3 ligase scaffold-repurposing BRD TRIM33 TRIM24 |
| url | https://www.mdpi.com/1422-0067/23/22/14218 |
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