Characterization of novel small molecule inhibitors of estrogen receptor-activation function 2 (ER-AF2).

ABSTRACT: Up to 40% of patients with estrogen receptor (ER)-positive breast cancer will develop resistance against the majority of current ER-directed therapies. Resistance can arise through various mechanisms such as increased expression levels of coregulators, and key mutations acquired in the receptor's ligand binding domain rendering it constitutively active. To overcome these resistance mechanisms, we explored targeting the ER Activation Function 2 (AF2) site, which is essential for coactivator binding and activation. Using artificial intelligence and the deep docking methodology, we virtually screened > 1 billion small molecules and identified 290 potential AF2 binders that were then characterized and validated through an iterative screening pipeline of cell-based and cell-free assays. We rank

SUBMITTER: Foo J 

PROVIDER: S-EPMC11590367 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature