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

Anil Kumar Devakrishnan; Chandrashekhar Madasu; Yong Wang; Ramkumar Modukuri; Kurt M Bohren; Kevin R MacKenzie; Damian W Young; Suzanne A W Fuqua; Martin M Matzuk; Murugesan Palaniappan

doi:10.1038/s41523-025-00837-5

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.

Authors

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. palaniap@bcm.edu.
⁸ Center for Drug Discovery, Baylor College of Medicine, Houston, TX, USA. palaniap@bcm.edu.
⁹ Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. palaniap@bcm.edu.

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.

Abstract

Grants and funding