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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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]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	BRAF kinase PROTACs encorafenib pomalidomide molecular dynamics

Übergeordnetes Werk:	In: Molecules - MDPI AG, 2003, 27(2022), 23, p 8513
Übergeordnetes Werk:	volume:27 ; year:2022 ; number:23, p 8513

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/molecules27238513

Katalog-ID:	DOAJ025571338

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allfields	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
spelling	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
allfieldsSound	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
language	English
source	In Molecules 27(2022), 23, p 8513 volume:27 year:2022 number:23, p 8513
sourceStr	In Molecules 27(2022), 23, p 8513 volume:27 year:2022 number:23, p 8513
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	BRAF kinase PROTACs encorafenib pomalidomide molecular dynamics Organic chemistry
isfreeaccess_bool	true
container_title	Molecules
authorswithroles_txt_mv	Elisabetta Marini @@aut@@ Marco Marino @@aut@@ Giulia Gionfriddo @@aut@@ Federica Maione @@aut@@ Marta Pandini @@aut@@ Daniele Oddo @@aut@@ Marta Giorgis @@aut@@ Barbara Rolando @@aut@@ Federica Blua @@aut@@ Simone Gastaldi @@aut@@ Serena Marchiò @@aut@@ Sandra Kovachka @@aut@@ Francesca Spyrakis @@aut@@ Eleonora Gianquinto @@aut@@ Federica Di Nicolantonio @@aut@@ Massimo Bertinaria @@aut@@
publishDateDaySort_date	2022-01-01T00:00:00Z
hierarchy_top_id	311313132
id	DOAJ025571338
language_de	englisch
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callnumber-first	Q - Science
author	Elisabetta Marini
spellingShingle	Elisabetta Marini misc QD241-441 misc BRAF kinase misc PROTACs misc encorafenib misc pomalidomide misc molecular dynamics misc Organic chemistry Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup<V600E</sup< Protein
authorStr	Elisabetta Marini
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topic_title	QD241-441 Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup<V600E</sup< Protein BRAF kinase PROTACs encorafenib pomalidomide molecular dynamics
topic	misc QD241-441 misc BRAF kinase misc PROTACs misc encorafenib misc pomalidomide misc molecular dynamics misc Organic chemistry
topic_unstemmed	misc QD241-441 misc BRAF kinase misc PROTACs misc encorafenib misc pomalidomide misc molecular dynamics misc Organic chemistry
topic_browse	misc QD241-441 misc BRAF kinase misc PROTACs misc encorafenib misc pomalidomide misc molecular dynamics misc Organic chemistry
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title	Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup<V600E</sup< Protein
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title_full	Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup<V600E</sup< Protein
author_sort	Elisabetta Marini
journal	Molecules
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author_browse	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
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title_sort	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.
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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
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up_date	2024-07-03T15:48:20.848Z
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Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAF<sup<V600E</sup< Protein

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