Conformational modulation of intrinsically disordered transactivation domains for cancer therapy

PNAS Nexus, Год журнала: 2025, Номер 4(5)

Опубликована: Апрель 30, 2025

Intrinsically disordered proteins are implicated in many diseases, but their overrepresentation among transcription factors, whose deregulation can cause disproportionate expression of oncogenes, suggests an important role cancer. Targeting factors for therapy is considered challenging, as they undergo dynamic transitions and exist ensemble interconverting states. This enables them to interact with multiple downstream partners, often through transactivation domains (TADs) by the mechanisms conformational selection, folding-upon-binding, or formation "fuzzy" complexes. The TAD interfaces, despite falling outside what "classical" binding pockets, be conformationally modulated interfere target recruitment hence represent potentially druggable sites. Here, we discuss structure-activity relationship TADs from p53, c-MYC, androgen receptor, progresses made modulating interactions small molecules. These recent advances highlight potential targeting these so far "undruggable" cancer therapy.

Язык: Английский

Emerging therapies to overcome antiandrogen resistance and beyond in lethal prostate cancer

Journal of the National Cancer Center, Год журнала: 2025, Номер unknown

Опубликована: Май 1, 2025

Язык: Английский

Androgen receptor signalling in non-prostatic malignancies: challenges and opportunities

Nature reviews. Cancer, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 25, 2024

Язык: Английский