{"doi":"10.1101/2020.12.01.406694","title":"Chemical inhibition of ENL/AF9 YEATS domains in acute leukemia","abstract":"Abstract Transcriptional co-regulators, which mediate chromatin-dependent transcriptional signaling, represent tractable targets to modulate tumorigenic gene expression programs with small molecules. Genetic loss-of-function studies have recently implicated the transcriptional co-activator, ENL, as a selective requirement for the survival of acute leukemia and highlighted an essential role for its chromatin reader YEATS domain. Motivated by these discoveries, we executed a screen of nearly 300,000 small molecules and identified an amido-imidazopyridine inhibitor of the ENL YEATS domain (IC 50 = 7 µM). Leveraging a SuFEx-based high-throughput approach to medicinal chemistry optimization, we discovered SR-0813 (IC 50 = 25 nM), a potent and selective ENL/AF9 YEATS domain inhibitor that exclusively inhibits the growth of ENL-dependent leukemia cell lines. Armed with this tool and a first-in-class ENL PROTAC, SR-1114, we detailed the response of AML cells to pharmacological ENL disruption for the first time. Most notably, displacement of ENL from chromatin by SR-0813 elicited a strikingly selective suppression of ENL target genes, including HOXA9/10, MYB, MYC and a number of other leukemia proto-oncogenes. Our study reproduces a number of key observations previously made by CRISPR/Cas9 loss of function and dTAG-mediated degradation, and therefore, both reinforces ENL as an emerging leukemia target and validates SR-0813 as a high-quality chemical probe.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":122391,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":116743,"name":"Timothy Bishop","orcid":"0000-0002-0321-7809","position":1,"is_corresponding":false},{"id":563491,"name":"Seiya Kitamura","orcid":"0000-0003-2453-849X","position":2,"is_corresponding":false},{"id":469464,"name":"Natalia Milosevich","orcid":"0000-0001-5708-6907","position":3,"is_corresponding":false},{"id":469463,"name":"Joshua N. Asiaban","orcid":"0000-0001-6425-012X","position":4,"is_corresponding":false},{"id":563492,"name":"Xiaoyu Zhang","orcid":"0000-0002-6617-6311","position":5,"is_corresponding":false},{"id":563493,"name":"Qinheng Zheng","orcid":"0000-0002-8440-8673","position":6,"is_corresponding":false},{"id":329380,"name":"Emily Chen","orcid":"0000-0001-7169-8192","position":7,"is_corresponding":false},{"id":491299,"name":"Anissa R. Ramos","orcid":null,"position":8,"is_corresponding":false},{"id":470532,"name":"Christopher J. Ackerman","orcid":null,"position":9,"is_corresponding":false},{"id":469467,"name":"Eric Hampton","orcid":"0000-0003-3104-3612","position":10,"is_corresponding":false},{"id":107932,"name":"Arnab K. Chatterjee","orcid":"0000-0001-5171-7982","position":11,"is_corresponding":false},{"id":469468,"name":"Travis S. Young","orcid":"0000-0001-8562-5736","position":12,"is_corresponding":false},{"id":107914,"name":"Mitchell Hull","orcid":"0000-0002-9364-1901","position":13,"is_corresponding":false},{"id":74387,"name":"K. Barry Sharpless","orcid":"0000-0001-6051-1599","position":14,"is_corresponding":false},{"id":236419,"name":"Benjamin F. Cravatt","orcid":"0000-0001-5330-3492","position":15,"is_corresponding":false},{"id":377193,"name":"Dennis W. Wolan","orcid":"0000-0001-9879-8353","position":16,"is_corresponding":false},{"id":116744,"name":"Michael A. Erb","orcid":"0000-0001-9993-3481","position":17,"is_corresponding":false},{"id":563490,"name":"Leopold Garnar-Wortzel","orcid":"0000-0001-5055-7817","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-18T23:14:51.076430Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}