{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE322nnn/GSE322892/"]},"type":"primary"},"statusCodeValue":200,"statusCode":"OK"}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE322892"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Novel hydrophobic tag degraders overcome endocrine-resistant breast cancer by recruiting HSP27-mediated E3 ligase complex for ERα proteasomal degradation","description":"Hydrophobic tag (HyT)-mediated protein degradation has emerged as a pivotal tool for targeted protein degradation (TPD), yet its underlying degradation mechanism remains incompletely elucidated. Herein, we designed structurally optimized HyT-based degraders by covalently conjugating hydrophobic amino acid tags to ERα-targeting ligands via alkane linkers of varying lengths, identifying the lead compound VI-10h. VI-10h exhibited potent antiproliferative activity and efficient ERα degradation in endocrine-resistant breast cancer cells (LCC2, MCF-7D538G, MCF-7Y537S, and MCF-7EGFR) and superior antitumor activity compared to the clinical drug fulvestrant (Ful) in MCF-7 and tamoxifen-resistant LCC2 xenograft models. To elucidate the HyT-mediated degradation mechanism, we synthesized biotin-conjugated HyTs (biotin-Lys and biotin-Trp) and performed pull-down assays combined with mass spectrometry. Our results unveiled that VI-10h selectively recruits HSP27 as a novel atypical E3 ligase adaptor protein, forms an ERα-HSP27-RING1 ternary complex to promote ERα degradation, disrupts estrogen-dependent oncogenic networks, and circumvents the drug resistance associated with conventional CRBN- or VHL-dependent E3 ligase-recruiting degraders. This study validates HyT technology’s degradation mechanism and feasibility in reversing resistance to conventional E3 ligases and overcoming endocrine-resistant breast cancer, establishing a molecular design strategy for next-generation targeted degraders that reverse endocrine resistance.","dates":{"publication":"2026/07/29"},"accession":"GSE322892","cross_references":{"GSM":["GSM9560576","GSM9560577","GSM9560578","GSM9560582","GSM9560583","GSM9560584","GSM9560580","GSM9560581","GSM9560579"],"GPL":["24676"],"GSE":["322892"],"taxon":["Homo sapiens"],"PMID":["[42189698]"]}}