biostudies-literatureUnknownZammit CMNCI NIH HHSNIH HHSAndrogen-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 identbioRxiv : the preprint server for biology2025.02.12.637117https://www.ebi.ac.uk/biostudies/studies/S-EPMC11844536biostudies-literatureCovalent Destabilizing Degrader of AR and AR-V7 in Androgen-Independent Prostate Cancer Cells.PMC11844536R01 CA240981S10 OD024998R35 CA263814Nomura DKKoirala SPotts PRLin YZammit CMNadel CMfalseCovalent Destabilizing Degrader of AR and AR-V7 in Androgen-Independent Prostate Cancer Cells.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 ident2025-01-01T00:00:00Z2025 Feb2026-04-29T03:15:47.733Z2025-04-06T02:38:59.378ZS-EPMC118445363999045810.1101/2025.02.12.637117