Discovery of a novel small molecule degrader of wild type and mutant estrogen receptors using DNA encoded libraries.

ABSTRACT: Estrogen receptor α (ERα) variants with mutations in the ligand binding domain (LBD) are less sensitive than wild type to standard-of-care drugs that bind ERα directly. To identify novel small-molecule drugs that target ERα mutants, we screened our multibillion-compound DNA-encoded libraries against ERα LBD variants. CDD-1274, which was highly enriched with all three variants, blocked spontaneous coactivator peptide recruitment to mutant ERα LBDs and inhibited estradiol-driven proliferative markers in several ER-positive breast cancer cell lines, but not in ER-negative breast cancer cells. We demonstrated that CDD-1274 induced proteasomal degradation of ERα variants in breast cancer cell lines and caused Y537S ERα degradation more effectively than elacestrant in a palbociclib-resistant cel

SUBMITTER: Devakrishnan AK 

PROVIDER: S-EPMC12612120 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature