| Autor: |
Shaon Basu, Paula Martínez-Cristóbal, Mireia Pesarrodona, Marta Frigolé-Vivas, Michael Lewis, Elzbieta Szulc, C. Adriana Bañuelos, Carolina Sánchez-Zarzalejo, Stasė Bielskutė, Jiaqi Zhu, Karina Pombo-García, Carla Garcia-Cabau, Cristina Batlle, Borja Mateos, Mateusz Biesaga, Albert Escobedo, Lídia Bardia, Xavier Verdaguer, Alessandro Ruffoni, Nasrin R. Mawji, Jun Wang, Teresa Tam, Isabelle Brun-Heath, Salvador Ventura, David Meierhofer, Jesús García, Paul Robustelli, Travis H. Stracker, Marianne D. Sadar, Antoni Riera, Denes Hnisz, Xavier Salvatella |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.08.18.504385 |
| Popis: |
SummaryTranscription factors are among the most attractive therapeutic targets but are considered largely undruggable 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 a transcription factor by allowing it to partition into transcriptional condensates. Based on this knowledge we optimized the structure of a small molecule inhibitor, previously identified by phenotypic screening, that targets a specific transactivation unit within the domain that is partially folded and rich in aromatic residues. The optimized compounds had more affinity for their target, inhibited androgen receptor-dependent transcriptional programs, and had antitumorigenic effect in models of castration-resistant prostate cancer in cells andin vivo. These results establish a generalizable framework to target small molecules to the activation domains of oncogenic transcription factors and other disease-associated proteins with therapeutic intent. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
