{"doi":"10.1021/acs.jmedchem.4c02445","title":"Discovery of Highly Potent and Orally Bioavailable Histone Deacetylase 3 Inhibitors as Immunomodulators and Enhancers of DNA-Damage Response in Cancer Therapy","abstract":"Histone deacetylase 3 (HDAC3) is a well-established target for cancer therapy. Herein, we developed <b>LSQ-28</b> as a novel HDAC3 inhibitor, which exhibited high HDAC3 inhibitory activity (IC<sub>50</sub> = 42 nM, SI > 161) and displayed potent antiproliferative activity against four cancer cells and further demonstrated excellent antimigratory, anti-invasive, and antiwound healing activities. Further studies revealed that <b>LSQ-28</b> induced a dose-dependent increase in Ac-H3 expression and promoted the degradation of PD-L1. Additionally, <b>LSQ-28</b> enhanced the DNA damage response induced by PARP inhibitor, as evidenced by regulated expression of PARP1 and γ-H2AX. Notably, <b>LSQ-28</b> also possessed favorable pharmacokinetic properties with significant oral bioavailability (<i>F</i> = 95.34%). Importantly, the combination of <b>LSQ-28</b> with the PD-L1 inhibitor NP-19 could enhance antitumor immune response (TGI = 80%). When combined with olaparib, <b>LSQ-28</b> significantly enhanced the in vivo tumor-suppression activity (TGI = 91%). Collectively, <b>LSQ-28</b> represents a promising HDAC3 inhibitor for further exploration in cancer therapeutic strategies.","journal":"Journal of Medicinal Chemistry","year":2025,"id":9950,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.049,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-28","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":85179,"name":"Zhihao Hu","orcid":"0000-0003-1558-9105","position":1,"is_corresponding":false},{"id":85180,"name":"Wanyi Pan","orcid":null,"position":2,"is_corresponding":false},{"id":85181,"name":"Haiyan Wu","orcid":null,"position":3,"is_corresponding":false},{"id":85182,"name":"Weijie Peng","orcid":"0000-0003-0019-010X","position":4,"is_corresponding":false},{"id":85183,"name":"Yi Wu","orcid":"0000-0003-2726-6135","position":5,"is_corresponding":false},{"id":85184,"name":"Feng Jiang","orcid":"0000-0001-5161-6153","position":6,"is_corresponding":false},{"id":51533,"name":"Xiaopeng Peng","orcid":"0000-0002-4434-0846","position":7,"is_corresponding":false},{"id":85178,"name":"Shuqing Li","orcid":null,"position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":null,"created_at":"2026-03-01T18:20:47.508186Z","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":[]}