Molecular pharmacology of SERDs in the setting of tamoxifen resistance

Molecular pharmacology of SERDs in the setting of tamoxifen resistance. Upon binding tamoxifen, ERα undergoes a specific conformational change that enables the presentation of protein-protein interaction surfaces for which in tamoxifen-sensitive cells there are no compatible coregulators. Thus, tamoxifen binding commits ER down a "nonproductive" pathway, an activity that manifests as antagonism. It is proposed that chronic administration of tamoxifen, however, results in the selection of a subpopulation of cells that express a compatible coactivator (CoA). In this manner the pharmacology of tamoxifen "switches" from that of an antagonist to an agonist. SERDs, like GDC-0810, have activity in the setting of tamoxifen resistance because they (a) function as high affinity competitive antagonists, (b) induce a conformational change that is incompatible with coregulator interactions, and (c) target the receptor for proteasomal degradation.