{"doi":"10.1002/ddr.70084","title":"Augmenting the Anti‐Leukemic Activity of the BCL‐2 Inhibitor Venetoclax Through Its Transformation Into Polypharmacologic Dual BCL‐2/HDAC1 and Dual BCL‐2/HDAC6 Inhibitors","abstract":"Motivated by the anti-leukemic synergy between histone deacetylase (HDAC) inhibitors and the FDA-approved BCL-2 inhibitor venetoclax, coupled with our interests in polypharmacology, we sought to bolster the anti-leukemic efficacy of the clinical drug by grafting HDAC1-selective or HDAC6-selective inhibitor motifs onto a solvent-accessible domain of venetoclax. We discovered multiple polypharmacological agents that both retained the potent BCL-2 inhibitory activity of venetoclax and effectively inhibited either HDAC1 or HDAC6 with excellent (up to 80-fold) selectivities for the desired HDAC isoform. In addition, relative to parental venetoclax, two of our lead compounds, BD-4-213 and AMC-4-154, exhibited superior activities against the acute myeloid leukemia cell line MV4;11 and an MV4;11 cell line engineered to overexpress BCL-2. Annexin-V assay results confirmed an on-target mechanism of apoptosis for these novel chimeric molecules. Efforts to further boost the HDAC1 or HDAC6 binding affinities and/or selectivities proved unsuccessful due to synthetic chemistry challenges and solubility problems, which may underscore the difficulties of polypharmacology approaches involving a large inhibitor, such as venetoclax.","journal":"Drug Development Research","year":2025,"id":521197,"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":0.9527,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":771230,"name":"Christian Eberly","orcid":null,"position":1,"is_corresponding":false},{"id":421309,"name":"Brandon Drennen","orcid":null,"position":2,"is_corresponding":false},{"id":932467,"name":"Christopher C. Goodis","orcid":null,"position":3,"is_corresponding":false},{"id":1392057,"name":"Zoe Wuyts","orcid":null,"position":4,"is_corresponding":false},{"id":474930,"name":"Curt I. Civin","orcid":"0000-0002-9555-4895","position":5,"is_corresponding":false},{"id":420254,"name":"Steven Fletcher","orcid":"0000-0002-4429-8334","position":6,"is_corresponding":false},{"id":428276,"name":"Alexandria M. Chan","orcid":"0000-0001-6196-3036","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T02:49:44.558743Z","pmid":"40370107","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":[]}