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<p>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. <b>CDD-1274</b>, 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 <b>CDD-1274</b> 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 <b>CDD-1274</b> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月12日

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  • 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

摘要

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.