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Rational optimization of a transcription factor activation domain inhibitor

ABSTRACT: Transcription factors are among the most attractive therapeutic targets but are considered largely undruggable. Here we provide evidence that small molecule-mediated partitioning of the androgen receptor, an oncogenic transcription factor, into phase-separated condensates has therapeutic effect in prostate cancer. We show that the phase separation capacity of the androgen receptor is driven by aromatic residues and short unstable helices in its intrinsically disordered activation domain. Based on this knowledge, we developed tool compounds that covalently attach aromatic moieties to cysteines in the receptors’ activation domain. The compounds enhanced partitioning of the receptor into condensates, facilitated degradation of the receptor, inhibited androgen receptor-dependent transcriptional programs, and had antitumorigenic effect in mouse models of prostate cancer and castration resistant prostate cancer. These results establish a generalizable framework to target the phase-separation capacity of intrinsically disordered regions in oncogenic transcription factors and other disease-associated proteins with therapeutic intent.

ORGANISM(S): Homo sapiens

PROVIDER: GSE206853 | GEO | 2023/06/24

REPOSITORIES: GEO

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Androgen receptor condensates as drug targets

Project description:Transcription factors are among the most attractive therapeutic targets but are considered largely undruggable. Here we provide evidence that small molecule-mediated partitioning of the androgen receptor, an oncogenic transcription factor, into phase-separated condensates has therapeutic effect in prostate cancer. We show that the phase separation capacity of the androgen receptor is driven by aromatic residues and short unstable helices in its intrinsically disordered activation domain. Based on this knowledge, we developed tool compounds that covalently attach aromatic moieties to cysteines in the receptors’ activation domain. The compounds enhanced partitioning of the receptor into condensates, facilitated degradation of the receptor, inhibited androgen receptor-dependent transcriptional programs, and had antitumorigenic effect in mouse models of prostate cancer and castration resistant prostate cancer. These results establish a generalizable framework to target the phase-separation capacity of intrinsically disordered regions in oncogenic transcription factors and other disease-associated proteins with therapeutic intent.

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