{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE325nnn/GSE325037/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"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=GSE325037"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Development of Oligo-PROTACs that target C/EBPα","description":"CCAAT/enhancer-binding protein alpha (C/EBPα) is a critical lineage-defining transcription factor and tumor suppressor. Despite its clinical significance in conditions like acute myeloid leukemia and hepatocellular carcinoma (HCC), C/EBPα has remained undruggable due to its intrinsically disordered regions and lack of small-molecule binding pockets. In this study, we describe the development of a novel oligo-PROTAC (O’PROTAC) strategy designed to achieve targeted degradation of endogenous C/EBPα. We designed and synthesized a 10-mer double-stranded DNA motif based on C/EBPα binding motif, conjugated via variable linkers to E3 ligase ligands Pomalidomide or VH-032. A total of six candidates were synthesized and evaluated in 3T3-J2 and Huh7 cell lines. We demonstrate that these O’PROTACs successfully localize to the nucleus and achieve dose-dependent degradation of C/EBPα, with the most potent candidates exhibiting sub-micromolar DC50 via lipofection delivery. Notably, this degradation occurred without inducing significant cytotoxicity. We observe a transcriptional shift consistent with loss of C/EBPα, including downregulation of cooperative factors involved in liver lineage specification and their downstream target gene. This work establishes O’PROTACs as a viable modality for targeting C/EBPα, offering a novel strategy to mechanistic investigation and future therapeutic targeting.","dates":{"publication":"2026/09/03"},"accession":"GSE325037","cross_references":{"GSM":["GSM9594341","GSM9594336","GSM9594337","GSM9594338","GSM9594339","GSM9594340"],"GPL":["34281"],"GSE":["325037"],"taxon":["Homo sapiens"],"PMID":["[42682201]"]}}