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...
Ausführliche Beschreibung
Autor*in: |
Elisabetta Marini [verfasserIn] Marco Marino [verfasserIn] Giulia Gionfriddo [verfasserIn] Federica Maione [verfasserIn] Marta Pandini [verfasserIn] Daniele Oddo [verfasserIn] Marta Giorgis [verfasserIn] Barbara Rolando [verfasserIn] Federica Blua [verfasserIn] Simone Gastaldi [verfasserIn] Serena Marchiò [verfasserIn] Sandra Kovachka [verfasserIn] Francesca Spyrakis [verfasserIn] Eleonora Gianquinto [verfasserIn] Federica Di Nicolantonio [verfasserIn] Massimo Bertinaria [verfasserIn] |
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E-Artikel |
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Sprache: |
Englisch |
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2022 |
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In: Molecules - MDPI AG, 2003, 27(2022), 23, p 8513 |
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Übergeordnetes Werk: |
volume:27 ; year:2022 ; number:23, p 8513 |
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DOI / URN: |
10.3390/molecules27238513 |
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Katalog-ID: |
DOAJ025571338 |
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520 | |a 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. | ||
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10.3390/molecules27238513 doi (DE-627)DOAJ025571338 (DE-599)DOAJ321ff11884e9491784732a391526bf64 DE-627 ger DE-627 rakwb eng QD241-441 Elisabetta Marini verfasserin aut Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup<V600E</sup< Protein 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. BRAF kinase PROTACs encorafenib pomalidomide molecular dynamics Organic chemistry Marco Marino verfasserin aut Giulia Gionfriddo verfasserin aut Federica Maione verfasserin aut Marta Pandini verfasserin aut Daniele Oddo verfasserin aut Marta Giorgis verfasserin aut Barbara Rolando verfasserin aut Federica Blua verfasserin aut Simone Gastaldi verfasserin aut Serena Marchiò verfasserin aut Sandra Kovachka verfasserin aut Francesca Spyrakis verfasserin aut Eleonora Gianquinto verfasserin aut Federica Di Nicolantonio verfasserin aut Massimo Bertinaria verfasserin aut In Molecules MDPI AG, 2003 27(2022), 23, p 8513 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:27 year:2022 number:23, p 8513 https://doi.org/10.3390/molecules27238513 kostenfrei https://doaj.org/article/321ff11884e9491784732a391526bf64 kostenfrei https://www.mdpi.com/1420-3049/27/23/8513 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 27 2022 23, p 8513 |
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10.3390/molecules27238513 doi (DE-627)DOAJ025571338 (DE-599)DOAJ321ff11884e9491784732a391526bf64 DE-627 ger DE-627 rakwb eng QD241-441 Elisabetta Marini verfasserin aut Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup<V600E</sup< Protein 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. BRAF kinase PROTACs encorafenib pomalidomide molecular dynamics Organic chemistry Marco Marino verfasserin aut Giulia Gionfriddo verfasserin aut Federica Maione verfasserin aut Marta Pandini verfasserin aut Daniele Oddo verfasserin aut Marta Giorgis verfasserin aut Barbara Rolando verfasserin aut Federica Blua verfasserin aut Simone Gastaldi verfasserin aut Serena Marchiò verfasserin aut Sandra Kovachka verfasserin aut Francesca Spyrakis verfasserin aut Eleonora Gianquinto verfasserin aut Federica Di Nicolantonio verfasserin aut Massimo Bertinaria verfasserin aut In Molecules MDPI AG, 2003 27(2022), 23, p 8513 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:27 year:2022 number:23, p 8513 https://doi.org/10.3390/molecules27238513 kostenfrei https://doaj.org/article/321ff11884e9491784732a391526bf64 kostenfrei https://www.mdpi.com/1420-3049/27/23/8513 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 27 2022 23, p 8513 |
allfields_unstemmed |
10.3390/molecules27238513 doi (DE-627)DOAJ025571338 (DE-599)DOAJ321ff11884e9491784732a391526bf64 DE-627 ger DE-627 rakwb eng QD241-441 Elisabetta Marini verfasserin aut Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup<V600E</sup< Protein 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. BRAF kinase PROTACs encorafenib pomalidomide molecular dynamics Organic chemistry Marco Marino verfasserin aut Giulia Gionfriddo verfasserin aut Federica Maione verfasserin aut Marta Pandini verfasserin aut Daniele Oddo verfasserin aut Marta Giorgis verfasserin aut Barbara Rolando verfasserin aut Federica Blua verfasserin aut Simone Gastaldi verfasserin aut Serena Marchiò verfasserin aut Sandra Kovachka verfasserin aut Francesca Spyrakis verfasserin aut Eleonora Gianquinto verfasserin aut Federica Di Nicolantonio verfasserin aut Massimo Bertinaria verfasserin aut In Molecules MDPI AG, 2003 27(2022), 23, p 8513 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:27 year:2022 number:23, p 8513 https://doi.org/10.3390/molecules27238513 kostenfrei https://doaj.org/article/321ff11884e9491784732a391526bf64 kostenfrei https://www.mdpi.com/1420-3049/27/23/8513 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 27 2022 23, p 8513 |
allfieldsGer |
10.3390/molecules27238513 doi (DE-627)DOAJ025571338 (DE-599)DOAJ321ff11884e9491784732a391526bf64 DE-627 ger DE-627 rakwb eng QD241-441 Elisabetta Marini verfasserin aut Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup<V600E</sup< Protein 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. BRAF kinase PROTACs encorafenib pomalidomide molecular dynamics Organic chemistry Marco Marino verfasserin aut Giulia Gionfriddo verfasserin aut Federica Maione verfasserin aut Marta Pandini verfasserin aut Daniele Oddo verfasserin aut Marta Giorgis verfasserin aut Barbara Rolando verfasserin aut Federica Blua verfasserin aut Simone Gastaldi verfasserin aut Serena Marchiò verfasserin aut Sandra Kovachka verfasserin aut Francesca Spyrakis verfasserin aut Eleonora Gianquinto verfasserin aut Federica Di Nicolantonio verfasserin aut Massimo Bertinaria verfasserin aut In Molecules MDPI AG, 2003 27(2022), 23, p 8513 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:27 year:2022 number:23, p 8513 https://doi.org/10.3390/molecules27238513 kostenfrei https://doaj.org/article/321ff11884e9491784732a391526bf64 kostenfrei https://www.mdpi.com/1420-3049/27/23/8513 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 27 2022 23, p 8513 |
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10.3390/molecules27238513 doi (DE-627)DOAJ025571338 (DE-599)DOAJ321ff11884e9491784732a391526bf64 DE-627 ger DE-627 rakwb eng QD241-441 Elisabetta Marini verfasserin aut Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup<V600E</sup< Protein 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. BRAF kinase PROTACs encorafenib pomalidomide molecular dynamics Organic chemistry Marco Marino verfasserin aut Giulia Gionfriddo verfasserin aut Federica Maione verfasserin aut Marta Pandini verfasserin aut Daniele Oddo verfasserin aut Marta Giorgis verfasserin aut Barbara Rolando verfasserin aut Federica Blua verfasserin aut Simone Gastaldi verfasserin aut Serena Marchiò verfasserin aut Sandra Kovachka verfasserin aut Francesca Spyrakis verfasserin aut Eleonora Gianquinto verfasserin aut Federica Di Nicolantonio verfasserin aut Massimo Bertinaria verfasserin aut In Molecules MDPI AG, 2003 27(2022), 23, p 8513 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:27 year:2022 number:23, p 8513 https://doi.org/10.3390/molecules27238513 kostenfrei https://doaj.org/article/321ff11884e9491784732a391526bf64 kostenfrei https://www.mdpi.com/1420-3049/27/23/8513 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 27 2022 23, p 8513 |
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investigation into the use of encorafenib to develop potential protacs directed against braf<sup<v600e</sup< protein |
callnumber |
QD241-441 |
title_auth |
Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup<V600E</sup< Protein |
abstract |
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. |
abstractGer |
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. |
abstract_unstemmed |
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. |
collection_details |
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container_issue |
23, p 8513 |
title_short |
Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup<V600E</sup< Protein |
url |
https://doi.org/10.3390/molecules27238513 https://doaj.org/article/321ff11884e9491784732a391526bf64 https://www.mdpi.com/1420-3049/27/23/8513 https://doaj.org/toc/1420-3049 |
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author2 |
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 |
author2Str |
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 |
ppnlink |
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callnumber-subject |
QD - Chemistry |
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doi_str |
10.3390/molecules27238513 |
callnumber-a |
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up_date |
2024-07-03T15:48:20.848Z |
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