Antagonists of the N-terminal domain (NTD) of the AR have been proposed to overcome the limitations of current antiandrogens regarding mutant ARs, by directly blocking AR function from protein surface, outside of the LBP. This direct blockade is thought to provide a more efficient strategy to avoid or overcome abnormal AR action during AWS, as well as allowing for more flexibility in structural modification without the space limitations of the rigid LBP.
Steroid receptors have similarities in gene sequences and protein structures, leading often to functional crosstalk among steroid receptors. One of the criteria for AR NTD antagonists is to achieve high degree of specificity for the AR. It is though important to realize that AR specificity does not necessarily translate in vivo, since NTD antagonists may also interact with protein targets other than AR.