Synthesis and Biological Activity of a VHL-Based PROTAC Specific for p38α
We report a series of small molecule proteolysis-targeting chimeras (PROTACs) that target the protein kinase p38α for degradation. These PROTACs are based on a ligand of the VHL E3 ubiquitin ligase, which is linked to an ATP competitive inhibitor of p38α. We provide evidence that these compounds can...
| Authors: | ; ; ; ; ; |
|---|---|
| Format: | Article |
| Status: | Published version |
| Publication date: | 2023 |
| Country: | España |
| Institution: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repository: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:2445/205161 |
| Online Access: | https://hdl.handle.net/2445/205161 |
| Access Level: | Open access |
| Keyword: | Proteïnes quinases Regulació cel·lular Protein kinases Cellular control mechanisms |
| _version_ | 1878741541809291265 |
|---|---|
| author | Cubillos Rojas, Mónica |
| author2 | Loren, Guillem Hakim, Yusuf Z. Verdaguer i Espaulella, Xavier Riera i Escalé, Antoni Nebreda, Àngel R. |
| author2_role | author author author author author |
| author_browse | Cubillos Rojas, Mónica Hakim, Yusuf Z. Loren, Guillem Nebreda, Àngel R. Riera i Escalé, Antoni Verdaguer i Espaulella, Xavier |
| author_facet | Cubillos Rojas, Mónica Loren, Guillem Hakim, Yusuf Z. Verdaguer i Espaulella, Xavier Riera i Escalé, Antoni Nebreda, Àngel R. |
| author_role | author |
| collection | Recercat. Dipósit de la Recerca de Catalunya |
| description | We report a series of small molecule proteolysis-targeting chimeras (PROTACs) that target the protein kinase p38α for degradation. These PROTACs are based on a ligand of the VHL E3 ubiquitin ligase, which is linked to an ATP competitive inhibitor of p38α. We provide evidence that these compounds can induce the specific degradation of p38α, but not p38β and other related kinases, at nanomolar concentrations in several mammalian cell lines. We also show that the p38α-specific PROTACs are soluble in aqueous solutions and therefore suitable for their administration to mice. Systemic administration of the PROTACs induces p38α degradation only in the liver, probably due to the PROTAC becoming inactivated in that organ, but upon local administration the PROTACs induce p38α degradation in mammary tumors. Our compounds provide an alternative to traditional chemical inhibitors for targeting p38α signaling in cultured cells and in vivo. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_e703fa1cb08069d97cf663383d6a7e8a |
| institution | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| instname_str | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:recercat.cat:2445/205161 |
| publishDate | 2023 |
| publishDateSort | 2023 |
| publisher | MDPI |
| publisherStr | MDPI |
| reponame_str | Recercat. Dipósit de la Recerca de Catalunya |
| spelling | Synthesis and Biological Activity of a VHL-Based PROTAC Specific for p38α Cubillos Rojas, Mónica Loren, Guillem Hakim, Yusuf Z. Verdaguer i Espaulella, Xavier Riera i Escalé, Antoni Nebreda, Àngel R. Proteïnes quinases Regulació cel·lular Protein kinases Cellular control mechanisms We report a series of small molecule proteolysis-targeting chimeras (PROTACs) that target the protein kinase p38α for degradation. These PROTACs are based on a ligand of the VHL E3 ubiquitin ligase, which is linked to an ATP competitive inhibitor of p38α. We provide evidence that these compounds can induce the specific degradation of p38α, but not p38β and other related kinases, at nanomolar concentrations in several mammalian cell lines. We also show that the p38α-specific PROTACs are soluble in aqueous solutions and therefore suitable for their administration to mice. Systemic administration of the PROTACs induces p38α degradation only in the liver, probably due to the PROTAC becoming inactivated in that organ, but upon local administration the PROTACs induce p38α degradation in mammary tumors. Our compounds provide an alternative to traditional chemical inhibitors for targeting p38α signaling in cultured cells and in vivo. MDPI https://hdl.handle.net/2445/205161 |
| spellingShingle | Synthesis and Biological Activity of a VHL-Based PROTAC Specific for p38α Cubillos Rojas, Mónica Proteïnes quinases Regulació cel·lular Protein kinases Cellular control mechanisms |
| status_str | publishedVersion |
| title | Synthesis and Biological Activity of a VHL-Based PROTAC Specific for p38α |
| title_full | Synthesis and Biological Activity of a VHL-Based PROTAC Specific for p38α |
| title_fullStr | Synthesis and Biological Activity of a VHL-Based PROTAC Specific for p38α |
| title_full_unstemmed | Synthesis and Biological Activity of a VHL-Based PROTAC Specific for p38α |
| title_short | Synthesis and Biological Activity of a VHL-Based PROTAC Specific for p38α |
| title_sort | Synthesis and Biological Activity of a VHL-Based PROTAC Specific for p38α |
| topic | Proteïnes quinases Regulació cel·lular Protein kinases Cellular control mechanisms |
| topic_facet | Proteïnes quinases Regulació cel·lular Protein kinases Cellular control mechanisms |
| url | https://hdl.handle.net/2445/205161 |