Covalent Destabilizing Degrader of AR and AR-V7 in Androgen-Independent Prostate Cancer Cells.

ABSTRACT: Androgen-independent prostate cancers, correlated with heightened aggressiveness and poor prognosis, are caused by mutations or deletions in the androgen receptor (AR) or expression of truncated variants of AR that are constitutively activated. Currently, drugs and drug candidates against AR target the steroid-binding domain to antagonize or degrade AR. However, these compounds cannot therapeutically access largely intrinsically disordered truncated splice variants of AR, such as AR-V7, that only possess the DNA binding domain and are missing the ligand binding domain. Targeting intrinsically disordered regions within transcription factors has remained challenging and is considered "undruggable". Herein, we leveraged a cysteine-reactive covalent ligand library in a cellular screen to ident

SUBMITTER: Zammit CM 

PROVIDER: S-EPMC11844536 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature