EPI-001, a compound active against castration-resistant prostate cancer, targets transactivation unit 5 of the androgen receptor

Castration-resistant prostate cancer is the lethal condition suffered by prostate cancer patients that become refractory to androgen deprivation therapy. EPI-001 is a recently identified compound active against this condition that modulates the activity of the androgen receptor, a nuclear receptor that is essential for disease progression. The mechanism by which this compound exerts its inhibitory activity is however not yet fully understood. Here we show, by using high resolution solution nuclear magnetic resonance spectroscopy, that EPI-001 selectively interacts with a partially folded region of the transactivation domain of the androgen receptor, known as transactivation unit 5, that is key for the ability of prostate cells to proliferate in the absence of androgens, a distinctive feature of castration-resistant prostate cancer. Our results can contribute to the development of more potent and less toxic novel androgen receptor antagonists for treating this disease

Structural insights into “acid blobs and negative noodles” – The androgen receptor as a case study

[eng] Androgen receptor is a transcription factor that plays a key role in prostate cancer development and progression. Its N-terminal intrinsically disordered activation domain is an example of ill- structured negatively charged "acid blob" or "negative noodle" described in 1988 by Paul B. Sigler. In his model the transcription pre-initiation complex formation relies on non-specific interactions between the "negative noodles" of the transcriptional activating proteins and hydroxyl groups of the heptapeptide repeats of the C-terminal domain in the largest subunit of RNA polymerase II. Here, we take advantage of various biophysical methods to understand the AR activation domain characteristics, its ability to undergo liquid-liquid phase separation and the importance of both for protein-protein interactions of the domain. We show relevance of the secondary structure elements in the AD function despite its general "acid blob" character