Rational optimization of a transcription factor activation domain inhibitor

Basu, Shaon|||0000-0003-2648-4827; Martínez-Cristóbal, Paula|||0000-0002-8464-3884; Frigolé-Vivas, Marta; Pesarrodona Roches, Mireia|||0000-0001-9669-8471; Lewis, Michael; Szulc, Elzbieta; Bañuelos, C. Adriana; Sánchez-Zarzalejo, Carolina|||0000-0002-7059-5658; Bielskutė, Stasė; Zhu, Jiaqi; Pombo-García, Karina|||0000-0002-2077-5909; Garcia-Cabau, Carla|||0000-0003-0533-0642; Zodi, Levente; Dockx, Hannes; Smak, Jordann; Kaur, Harpreet|||0000-0003-0421-8341; Batlle Carreras, Cristina|||0000-0003-4903-831X; Mateos, Borja|||0000-0002-0310-4943; Biesaga, Mateusz|||0000-0001-6443-1270; Escobedo, Albert|||0000-0001-7295-5111; Bardia, Lídia; Verdaguer, Xavier|||0000-0002-9229-969X; Ruffoni, Alessandro|||0000-0001-8617-2548; Mawji, Nasrin R.; Wang, Jun; Obst, Jon K.; Tam, Teresa; Brun-Heath, Isabelle|||0000-0002-5828-0020; Ventura, Salvador|||0000-0002-9652-6351; Meierhofer, David|||0000-0002-0170-868X; García, Jesús|||0000-0003-2961-9790; Robustelli, Paul|||0000-0002-9282-8993; Stracker, Travis H.|||0000-0002-8650-2081; Sadar, Marianne D.|||0000-0003-0599-9215; Riera, Antoni|||0000-0001-7142-7675; Hnisz, Denes|||0000-0002-6256-1693; Salvatella, Xavier|||0000-0002-8371-4185

Rational optimization of a transcription factor activation domain inhibitor

Transcription factors are among the most attractive therapeutic targets but are considered largely 'undruggable' in part due to the intrinsically disordered nature of their activation domains. Here we show that the aromatic character of the activation domain of the androgen receptor, a the...

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Autores:	Basu, Shaon\|\|\|0000-0003-2648-4827, Martínez-Cristóbal, Paula\|\|\|0000-0002-8464-3884, Frigolé-Vivas, Marta, Pesarrodona Roches, Mireia\|\|\|0000-0001-9669-8471, Lewis, Michael, Szulc, Elzbieta, Bañuelos, C. Adriana, Sánchez-Zarzalejo, Carolina\|\|\|0000-0002-7059-5658, Bielskutė, Stasė, Zhu, Jiaqi, Pombo-García, Karina\|\|\|0000-0002-2077-5909, Garcia-Cabau, Carla\|\|\|0000-0003-0533-0642, Zodi, Levente, Dockx, Hannes, Smak, Jordann, Kaur, Harpreet\|\|\|0000-0003-0421-8341, Batlle Carreras, Cristina\|\|\|0000-0003-4903-831X, Mateos, Borja\|\|\|0000-0002-0310-4943, Biesaga, Mateusz\|\|\|0000-0001-6443-1270, Escobedo, Albert\|\|\|0000-0001-7295-5111, Bardia, Lídia, Verdaguer, Xavier\|\|\|0000-0002-9229-969X, Ruffoni, Alessandro\|\|\|0000-0001-8617-2548, Mawji, Nasrin R., Wang, Jun, Obst, Jon K., Tam, Teresa, Brun-Heath, Isabelle\|\|\|0000-0002-5828-0020, Ventura, Salvador\|\|\|0000-0002-9652-6351, Meierhofer, David\|\|\|0000-0002-0170-868X, García, Jesús\|\|\|0000-0003-2961-9790, Robustelli, Paul\|\|\|0000-0002-9282-8993, Stracker, Travis H.\|\|\|0000-0002-8650-2081, Sadar, Marianne D.\|\|\|0000-0003-0599-9215, Riera, Antoni\|\|\|0000-0001-7142-7675, Hnisz, Denes\|\|\|0000-0002-6256-1693, Salvatella, Xavier\|\|\|0000-0002-8371-4185
Tipo de recurso:	artículo
Fecha de publicación:	2023
País:	España
Institución:	Universitat Autònoma de Barcelona
Repositorio:	Dipòsit Digital de Documents de la UAB
Idioma:	inglés
OAI Identifier:	oai:ddd.uab.cat:307791
Acceso en línea:	https://ddd.uab.cat/record/307791 https://dx.doi.org/urn:doi:10.1038/s41594-023-01159-5
Access Level:	acceso abierto
Palabra clave:	Intrinsically disordered proteins Drug discovery Protein aggregation

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network_acronym_str	ES
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repository_id_str
spelling	Rational optimization of a transcription factor activation domain inhibitorBasu, Shaon\|\|\|0000-0003-2648-4827Martínez-Cristóbal, Paula\|\|\|0000-0002-8464-3884Frigolé-Vivas, MartaPesarrodona Roches, Mireia\|\|\|0000-0001-9669-8471Lewis, MichaelSzulc, ElzbietaBañuelos, C. AdrianaSánchez-Zarzalejo, Carolina\|\|\|0000-0002-7059-5658Bielskutė, StasėZhu, JiaqiPombo-García, Karina\|\|\|0000-0002-2077-5909Garcia-Cabau, Carla\|\|\|0000-0003-0533-0642Zodi, LeventeDockx, HannesSmak, JordannKaur, Harpreet\|\|\|0000-0003-0421-8341Batlle Carreras, Cristina\|\|\|0000-0003-4903-831XMateos, Borja\|\|\|0000-0002-0310-4943Biesaga, Mateusz\|\|\|0000-0001-6443-1270Escobedo, Albert\|\|\|0000-0001-7295-5111Bardia, LídiaVerdaguer, Xavier\|\|\|0000-0002-9229-969XRuffoni, Alessandro\|\|\|0000-0001-8617-2548Mawji, Nasrin R.Wang, JunObst, Jon K.Tam, TeresaBrun-Heath, Isabelle\|\|\|0000-0002-5828-0020Ventura, Salvador\|\|\|0000-0002-9652-6351Meierhofer, David\|\|\|0000-0002-0170-868XGarcía, Jesús\|\|\|0000-0003-2961-9790Robustelli, Paul\|\|\|0000-0002-9282-8993Stracker, Travis H.\|\|\|0000-0002-8650-2081Sadar, Marianne D.\|\|\|0000-0003-0599-9215Riera, Antoni\|\|\|0000-0001-7142-7675Hnisz, Denes\|\|\|0000-0002-6256-1693Salvatella, Xavier\|\|\|0000-0002-8371-4185Intrinsically disordered proteinsDrug discoveryProtein aggregationTranscription factors are among the most attractive therapeutic targets but are considered largely 'undruggable' in part due to the intrinsically disordered nature of their activation domains. Here we show that the aromatic character of the activation domain of the androgen receptor, a therapeutic target for castration-resistant prostate cancer, is key for its activity as transcription factor, allowing it to translocate to the nucleus and partition into transcriptional condensates upon activation by androgens. On the basis of our understanding of the interactions stabilizing such condensates and of the structure that the domain adopts upon condensation, we optimized the structure of a small-molecule inhibitor previously identified by phenotypic screening. The optimized compounds had more affinity for their target, inhibited androgen-receptor-dependent transcriptional programs, and had an antitumorigenic effect in models of castration-resistant prostate cancer in cells and in vivo. These results suggest that it is possible to rationally optimize, and potentially even to design, small molecules that target the activation domains of oncogenic transcription factors. 22023-01-0120232023-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/307791https://dx.doi.org/urn:doi:10.1038/s41594-023-01159-5reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengEuropean Commission https://doi.org/10.13039/501100000780 754558Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2017/SGR-324Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 BIO2015-70092-RAgencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2019-110198RB-I00"la Caixa" Foundation https://doi.org/10.13039/100010434 CI20-00098European Commission https://doi.org/10.13039/501100000780 648201Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2020-115074GB-I00open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:3077912026-06-06T12:50:31Z
dc.title.none.fl_str_mv	Rational optimization of a transcription factor activation domain inhibitor
title	Rational optimization of a transcription factor activation domain inhibitor
spellingShingle	Rational optimization of a transcription factor activation domain inhibitor Basu, Shaon\|\|\|0000-0003-2648-4827 Intrinsically disordered proteins Drug discovery Protein aggregation
title_short	Rational optimization of a transcription factor activation domain inhibitor
title_full	Rational optimization of a transcription factor activation domain inhibitor
title_fullStr	Rational optimization of a transcription factor activation domain inhibitor
title_full_unstemmed	Rational optimization of a transcription factor activation domain inhibitor
title_sort	Rational optimization of a transcription factor activation domain inhibitor
dc.creator.none.fl_str_mv	Basu, Shaon\|\|\|0000-0003-2648-4827 Martínez-Cristóbal, Paula\|\|\|0000-0002-8464-3884 Frigolé-Vivas, Marta Pesarrodona Roches, Mireia\|\|\|0000-0001-9669-8471 Lewis, Michael Szulc, Elzbieta Bañuelos, C. Adriana Sánchez-Zarzalejo, Carolina\|\|\|0000-0002-7059-5658 Bielskutė, Stasė Zhu, Jiaqi Pombo-García, Karina\|\|\|0000-0002-2077-5909 Garcia-Cabau, Carla\|\|\|0000-0003-0533-0642 Zodi, Levente Dockx, Hannes Smak, Jordann Kaur, Harpreet\|\|\|0000-0003-0421-8341 Batlle Carreras, Cristina\|\|\|0000-0003-4903-831X Mateos, Borja\|\|\|0000-0002-0310-4943 Biesaga, Mateusz\|\|\|0000-0001-6443-1270 Escobedo, Albert\|\|\|0000-0001-7295-5111 Bardia, Lídia Verdaguer, Xavier\|\|\|0000-0002-9229-969X Ruffoni, Alessandro\|\|\|0000-0001-8617-2548 Mawji, Nasrin R. Wang, Jun Obst, Jon K. Tam, Teresa Brun-Heath, Isabelle\|\|\|0000-0002-5828-0020 Ventura, Salvador\|\|\|0000-0002-9652-6351 Meierhofer, David\|\|\|0000-0002-0170-868X García, Jesús\|\|\|0000-0003-2961-9790 Robustelli, Paul\|\|\|0000-0002-9282-8993 Stracker, Travis H.\|\|\|0000-0002-8650-2081 Sadar, Marianne D.\|\|\|0000-0003-0599-9215 Riera, Antoni\|\|\|0000-0001-7142-7675 Hnisz, Denes\|\|\|0000-0002-6256-1693 Salvatella, Xavier\|\|\|0000-0002-8371-4185
author	Basu, Shaon\|\|\|0000-0003-2648-4827
author_facet	Basu, Shaon\|\|\|0000-0003-2648-4827 Martínez-Cristóbal, Paula\|\|\|0000-0002-8464-3884 Frigolé-Vivas, Marta Pesarrodona Roches, Mireia\|\|\|0000-0001-9669-8471 Lewis, Michael Szulc, Elzbieta Bañuelos, C. Adriana Sánchez-Zarzalejo, Carolina\|\|\|0000-0002-7059-5658 Bielskutė, Stasė Zhu, Jiaqi Pombo-García, Karina\|\|\|0000-0002-2077-5909 Garcia-Cabau, Carla\|\|\|0000-0003-0533-0642 Zodi, Levente Dockx, Hannes Smak, Jordann Kaur, Harpreet\|\|\|0000-0003-0421-8341 Batlle Carreras, Cristina\|\|\|0000-0003-4903-831X Mateos, Borja\|\|\|0000-0002-0310-4943 Biesaga, Mateusz\|\|\|0000-0001-6443-1270 Escobedo, Albert\|\|\|0000-0001-7295-5111 Bardia, Lídia Verdaguer, Xavier\|\|\|0000-0002-9229-969X Ruffoni, Alessandro\|\|\|0000-0001-8617-2548 Mawji, Nasrin R. Wang, Jun Obst, Jon K. Tam, Teresa Brun-Heath, Isabelle\|\|\|0000-0002-5828-0020 Ventura, Salvador\|\|\|0000-0002-9652-6351 Meierhofer, David\|\|\|0000-0002-0170-868X García, Jesús\|\|\|0000-0003-2961-9790 Robustelli, Paul\|\|\|0000-0002-9282-8993 Stracker, Travis H.\|\|\|0000-0002-8650-2081 Sadar, Marianne D.\|\|\|0000-0003-0599-9215 Riera, Antoni\|\|\|0000-0001-7142-7675 Hnisz, Denes\|\|\|0000-0002-6256-1693 Salvatella, Xavier\|\|\|0000-0002-8371-4185
author_role	author
author2	Martínez-Cristóbal, Paula\|\|\|0000-0002-8464-3884 Frigolé-Vivas, Marta Pesarrodona Roches, Mireia\|\|\|0000-0001-9669-8471 Lewis, Michael Szulc, Elzbieta Bañuelos, C. Adriana Sánchez-Zarzalejo, Carolina\|\|\|0000-0002-7059-5658 Bielskutė, Stasė Zhu, Jiaqi Pombo-García, Karina\|\|\|0000-0002-2077-5909 Garcia-Cabau, Carla\|\|\|0000-0003-0533-0642 Zodi, Levente Dockx, Hannes Smak, Jordann Kaur, Harpreet\|\|\|0000-0003-0421-8341 Batlle Carreras, Cristina\|\|\|0000-0003-4903-831X Mateos, Borja\|\|\|0000-0002-0310-4943 Biesaga, Mateusz\|\|\|0000-0001-6443-1270 Escobedo, Albert\|\|\|0000-0001-7295-5111 Bardia, Lídia Verdaguer, Xavier\|\|\|0000-0002-9229-969X Ruffoni, Alessandro\|\|\|0000-0001-8617-2548 Mawji, Nasrin R. Wang, Jun Obst, Jon K. Tam, Teresa Brun-Heath, Isabelle\|\|\|0000-0002-5828-0020 Ventura, Salvador\|\|\|0000-0002-9652-6351 Meierhofer, David\|\|\|0000-0002-0170-868X García, Jesús\|\|\|0000-0003-2961-9790 Robustelli, Paul\|\|\|0000-0002-9282-8993 Stracker, Travis H.\|\|\|0000-0002-8650-2081 Sadar, Marianne D.\|\|\|0000-0003-0599-9215 Riera, Antoni\|\|\|0000-0001-7142-7675 Hnisz, Denes\|\|\|0000-0002-6256-1693 Salvatella, Xavier\|\|\|0000-0002-8371-4185
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	Intrinsically disordered proteins Drug discovery Protein aggregation
topic	Intrinsically disordered proteins Drug discovery Protein aggregation
description	Transcription factors are among the most attractive therapeutic targets but are considered largely 'undruggable' in part due to the intrinsically disordered nature of their activation domains. Here we show that the aromatic character of the activation domain of the androgen receptor, a therapeutic target for castration-resistant prostate cancer, is key for its activity as transcription factor, allowing it to translocate to the nucleus and partition into transcriptional condensates upon activation by androgens. On the basis of our understanding of the interactions stabilizing such condensates and of the structure that the domain adopts upon condensation, we optimized the structure of a small-molecule inhibitor previously identified by phenotypic screening. The optimized compounds had more affinity for their target, inhibited androgen-receptor-dependent transcriptional programs, and had an antitumorigenic effect in models of castration-resistant prostate cancer in cells and in vivo. These results suggest that it is possible to rationally optimize, and potentially even to design, small molecules that target the activation domains of oncogenic transcription factors.
publishDate	2023
dc.date.none.fl_str_mv	2 2023-01-01 2023 2023-01-01
dc.type.none.fl_str_mv	Article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	https://ddd.uab.cat/record/307791 https://dx.doi.org/urn:doi:10.1038/s41594-023-01159-5
url	https://ddd.uab.cat/record/307791 https://dx.doi.org/urn:doi:10.1038/s41594-023-01159-5
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.relation.none.fl_str_mv	European Commission https://doi.org/10.13039/501100000780 754558 Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2017/SGR-324 Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 BIO2015-70092-R Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2019-110198RB-I00 "la Caixa" Foundation https://doi.org/10.13039/100010434 CI20-00098 European Commission https://doi.org/10.13039/501100000780 648201 Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2020-115074GB-I00
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.source.none.fl_str_mv	reponame:Dipòsit Digital de Documents de la UAB instname:Universitat Autònoma de Barcelona
instname_str	Universitat Autònoma de Barcelona
reponame_str	Dipòsit Digital de Documents de la UAB
collection	Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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Rational optimization of a transcription factor activation domain inhibitor

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