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

  • NPJ Breast Cancer. 2025 Nov 12;11(1):125. doi: 10.1038/s41523-025-00837-5.
Anil Kumar Devakrishnan  1  2 ,  Chandrashekhar Madasu  1  2 ,  Yong Wang  1  2 ,  Ramkumar Modukuri  1  2 ,  Kurt M Bohren  1  2 ,  Kevin R MacKenzie  1  2  3 ,  Damian W Young  1  2  3 ,  Suzanne A W Fuqua  4  5  6 ,  Martin M Matzuk  1  2  3 ,  Murugesan Palaniappan  7  8  9
Affiliations
  • 1. Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA.
  • 2. Center for Drug Discovery, Baylor College of Medicine, Houston, TX, USA.
  • 3. Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA.
  • 4. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
  • 5. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
  • 6. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
  • 7. Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 8. Center for Drug Discovery, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 9. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. [email protected].
PMID: 41224743 DOI: 10.1038/s41523-025-00837-5
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.

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