UT-34 is a potent, second-generation androgen receptor (AR) pan antagonist, degrades enzalutamide-sensitive and -resistant ARs and AR splice variants (AR-SVs).
UT-34 interacts with AR AF-1 domain, UT-34 does not bind to the AR-LBD.
UT-34 antagonizes the wild-type AR with IC50 of 200 nM, inhibits the various mutant ARs (W741L, T877A, and F876L) comparably or with better IC50.
UT-34 downregulates T877A-AR and F876L-enzalutamide-resistant AR, reduces AR levels at 1 uM in LNCaP and MR49F cells.
UT-34 does not inhibit the transactivation of GR and mineralocorticoid receptor, and does not downregulate the ER and PR protein levels.
UT-34 requires ubiquitin proteasome pathway to degrade the AR.
UT-34 promotes AR-V7 degradation, inhibits AR and AR-V7-target gene expression and induces distinct AR conformation.
UT-34 inhibits enzalutamide-sensitive and -resistant AR-dependent gene expression and prostate cancer cell proliferation.
UT-34 inhibits AR function and proliferation of an AR-amplified model (VCaP cells) and a PDX model.