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
Descripción
Sumario: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.

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