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Rational optimization of a transcription factor activation domain inhibitor.

Shaon BasuPaula Martínez-CristóbalMarta Frigolé-VivasMireia PesarrodonaMichael LewisElzbieta SzulcC Adriana BañuelosCarolina Sánchez-ZarzalejoStasė BielskutėJiaqi ZhuKarina Pombo-GarcíaCarla Garcia-CabauLevente ZodiHannes DockxJordann SmakHarpreet KaurCristina BatlleBorja MateosMateusz BiesagaAlbert EscobedoLídia BardiaXavier VerdaguerAlessandro RuffoniNasrin R MawjiJun WangJon K ObstTeresa TamIsabelle Brun HeathSalvador VenturaDavid MeierhoferJesús GarcíaPaul RobustelliTravis H StrackerMarianne D SadarAntoni RieraDenes HniszXavier Salvatella
Published in: Nature structural & molecular biology (2023)
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.
Keyphrases
  • transcription factor
  • small molecule
  • dna binding
  • gene expression
  • public health
  • genome wide identification
  • induced apoptosis
  • signaling pathway
  • cell proliferation
  • heat shock
  • capillary electrophoresis