Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup>V600E</sup> Protein
BRAF is a serine/threonine kinase frequently mutated in human cancers. BRAF<sup>V600E</sup> mutated protein is targeted through the use of kinase inhibitors which are approved for the treatment of melanoma; however, their long-term efficacy is hampered by resistance mechanisms. The PROTA...
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| Format: | Article |
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MDPI AG
2022-12-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/23/8513 |
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| author | Elisabetta Marini Marco Marino Giulia Gionfriddo Federica Maione Marta Pandini Daniele Oddo Marta Giorgis Barbara Rolando Federica Blua Simone Gastaldi Serena Marchiò Sandra Kovachka Francesca Spyrakis Eleonora Gianquinto Federica Di Nicolantonio Massimo Bertinaria |
| author_facet | Elisabetta Marini Marco Marino Giulia Gionfriddo Federica Maione Marta Pandini Daniele Oddo Marta Giorgis Barbara Rolando Federica Blua Simone Gastaldi Serena Marchiò Sandra Kovachka Francesca Spyrakis Eleonora Gianquinto Federica Di Nicolantonio Massimo Bertinaria |
| author_sort | Elisabetta Marini |
| collection | DOAJ |
| description | BRAF is a serine/threonine kinase frequently mutated in human cancers. BRAF<sup>V600E</sup> mutated protein is targeted through the use of kinase inhibitors which are approved for the treatment of melanoma; however, their long-term efficacy is hampered by resistance mechanisms. The PROTAC-induced degradation of BRAF<sup>V600E</sup> has been proposed as an alternative strategy to avoid the onset of resistance. In this study, we designed a series of compounds where the BRAF kinase inhibitor encorafenib was conjugated to pomalidomide through different linkers. The synthesized compounds maintained their ability to inhibit the kinase activity of mutated BRAF with IC<sub>50</sub> values in the 40–88 nM range. Selected compounds inhibited BRAF<sup>V600E</sup> signaling and cellular proliferation of A375 and Colo205 tumor cell lines. Compounds <b>10</b> and <b>11</b>, the most active of the series, were not able to induce degradation of mutated BRAF. Docking and molecular dynamic studies, conducted in comparison with the efficient BRAF degrader P5B, suggest that a different orientation of the linker bearing the pomalidomide substructure, together with a decreased mobility of the solvent-exposed part of the conjugates, could explain this behavior. |
| first_indexed | 2024-03-09T17:38:29Z |
| format | Article |
| id | doaj.art-321ff11884e9491784732a391526bf64 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T17:38:29Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-321ff11884e9491784732a391526bf642023-11-24T11:43:30ZengMDPI AGMolecules1420-30492022-12-012723851310.3390/molecules27238513Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup>V600E</sup> ProteinElisabetta Marini0Marco Marino1Giulia Gionfriddo2Federica Maione3Marta Pandini4Daniele Oddo5Marta Giorgis6Barbara Rolando7Federica Blua8Simone Gastaldi9Serena Marchiò10Sandra Kovachka11Francesca Spyrakis12Eleonora Gianquinto13Federica Di Nicolantonio14Massimo Bertinaria15Department of Drug Science and Technology, University of Turin, 10125 Torino, ItalyDepartment of Drug Science and Technology, University of Turin, 10125 Torino, ItalyCandiolo Cancer Institute, FPO-IRCCS (Fondazione del Piemonte per l’Oncologia-Istituti di Ricovero e Cura a Carattere Scientifico), 10060 Candiolo, ItalyCandiolo Cancer Institute, FPO-IRCCS (Fondazione del Piemonte per l’Oncologia-Istituti di Ricovero e Cura a Carattere Scientifico), 10060 Candiolo, ItalyCandiolo Cancer Institute, FPO-IRCCS (Fondazione del Piemonte per l’Oncologia-Istituti di Ricovero e Cura a Carattere Scientifico), 10060 Candiolo, ItalyCandiolo Cancer Institute, FPO-IRCCS (Fondazione del Piemonte per l’Oncologia-Istituti di Ricovero e Cura a Carattere Scientifico), 10060 Candiolo, ItalyDepartment of Drug Science and Technology, University of Turin, 10125 Torino, ItalyDepartment of Drug Science and Technology, University of Turin, 10125 Torino, ItalyDepartment of Drug Science and Technology, University of Turin, 10125 Torino, ItalyDepartment of Drug Science and Technology, University of Turin, 10125 Torino, ItalyCandiolo Cancer Institute, FPO-IRCCS (Fondazione del Piemonte per l’Oncologia-Istituti di Ricovero e Cura a Carattere Scientifico), 10060 Candiolo, ItalyDepartment of Drug Science and Technology, University of Turin, 10125 Torino, ItalyDepartment of Drug Science and Technology, University of Turin, 10125 Torino, ItalyDepartment of Drug Science and Technology, University of Turin, 10125 Torino, ItalyCandiolo Cancer Institute, FPO-IRCCS (Fondazione del Piemonte per l’Oncologia-Istituti di Ricovero e Cura a Carattere Scientifico), 10060 Candiolo, ItalyDepartment of Drug Science and Technology, University of Turin, 10125 Torino, ItalyBRAF is a serine/threonine kinase frequently mutated in human cancers. BRAF<sup>V600E</sup> mutated protein is targeted through the use of kinase inhibitors which are approved for the treatment of melanoma; however, their long-term efficacy is hampered by resistance mechanisms. The PROTAC-induced degradation of BRAF<sup>V600E</sup> has been proposed as an alternative strategy to avoid the onset of resistance. In this study, we designed a series of compounds where the BRAF kinase inhibitor encorafenib was conjugated to pomalidomide through different linkers. The synthesized compounds maintained their ability to inhibit the kinase activity of mutated BRAF with IC<sub>50</sub> values in the 40–88 nM range. Selected compounds inhibited BRAF<sup>V600E</sup> signaling and cellular proliferation of A375 and Colo205 tumor cell lines. Compounds <b>10</b> and <b>11</b>, the most active of the series, were not able to induce degradation of mutated BRAF. Docking and molecular dynamic studies, conducted in comparison with the efficient BRAF degrader P5B, suggest that a different orientation of the linker bearing the pomalidomide substructure, together with a decreased mobility of the solvent-exposed part of the conjugates, could explain this behavior.https://www.mdpi.com/1420-3049/27/23/8513BRAF kinasePROTACsencorafenibpomalidomidemolecular dynamics |
| spellingShingle | Elisabetta Marini Marco Marino Giulia Gionfriddo Federica Maione Marta Pandini Daniele Oddo Marta Giorgis Barbara Rolando Federica Blua Simone Gastaldi Serena Marchiò Sandra Kovachka Francesca Spyrakis Eleonora Gianquinto Federica Di Nicolantonio Massimo Bertinaria Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup>V600E</sup> Protein Molecules BRAF kinase PROTACs encorafenib pomalidomide molecular dynamics |
| title | Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup>V600E</sup> Protein |
| title_full | Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup>V600E</sup> Protein |
| title_fullStr | Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup>V600E</sup> Protein |
| title_full_unstemmed | Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup>V600E</sup> Protein |
| title_short | Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup>V600E</sup> Protein |
| title_sort | investigation into the use of encorafenib to develop potential protacs directed against braf sup v600e sup protein |
| topic | BRAF kinase PROTACs encorafenib pomalidomide molecular dynamics |
| url | https://www.mdpi.com/1420-3049/27/23/8513 |
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