Language
English
Publication Date
11-12-2025
Journal
NPJ Breast Cancer
DOI
10.1038/s41523-025-00837-5
PMID
41224743
PMCID
PMC12612120
PubMedCentral® Posted Date
11-12-2025
PubMedCentral® Full Text Version
Post-print
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 cell line. These findings establish that CDD-1274 potently blocks ligand-dependent and ligand-independent ER signaling in endocrine-resistant breast cancer cells and could be further optimized for developing a new class of ERα degraders for endocrine therapy-resistant breast cancer.
Published Open-Access
yes
Recommended Citation
Devakrishnan, Anil Kumar; Madasu, Chandrashekhar; Wang, Yong; et al., "Discovery of a Novel Small Molecule Degrader of Wild Type and Mutant Estrogen Receptors Using DNA Encoded Libraries" (2025). Faculty and Staff Publications. 4610.
https://digitalcommons.library.tmc.edu/baylor_docs/4610