Pharmacodynamics<unk>  is a mixture of four stereoisomers.<unk>  binds to the activation function-1 (AF-1) region in the NTD of the AR, as opposed to other AR antagonists, which bind to the C-terminal LBD. A functional AF-1 is essential for the AR to have transcriptional activity. If AF-1 is deleted or mutated, the AR will still bind androgens, but will have no transcriptional activity. Importantly, if the AR lacks an LBD, the receptor will be nuclear and constitutively-active. Constitutively active splice variants of the AR that lack the C-terminal LBD are correlated to CRPC and poor survival.<unk>  is an inhibitor of constitutively active splice variant of ARs that lack the C-terminal LBD. Conventional antiandrogens do not inhibit constitutively-active variants of AR that have a truncated or deleted C-terminal LBD. In the absence of androgen, all known antiandrogens cause translocation of AR from the cytoplasm to the nucleus, whereas<unk>  does not cause the AR to become nuclear. Binding of<unk>  to the NTD of the AR blocks protein-protein interactions that are essential for its transcriptional activity. Specifically,<unk>  blocks AR interactions with CREB-binding protein, RAP74, and between the NTD and C-terminal domain (termed N/C interaction) required for antiparallel dimer formation of AR. Unlike antiandrogens such as bicalutamide,<unk>  does not cause the AR to bind to androgen response elements on the DNA of target genes.<unk>  at extremely high concentrations of 50 to 200 uM has also been found to act as a selective PPARγ modulator (SPPARM), with both agonistic and antagonistic actions on the PPARγ. Via PPARγ activation,<unk>  has been found to inhibit AR expression and activity in prostate cancer cells, indicating at least one AR-independent action by which<unk>  exhibits antiandrogen properties in the prostate.<unk>  inhibits AR-dependent proliferation of human prostate cancer cells while having no significant effects on cells that do not require the AR for growth and survival.<unk>  has specificity to the AR (aside from the PPARγ) and has excellent anti-tumor activity in vivo with xenografts of CRPC.
EPI-001
ESKAPE
WikEM
SmiNet
SmeT
ID2020
SAV001
IEC 62304