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Herein, we employed a fragment\u2010centric structure\u2010based design platform, leading to the discovery of\n                    <jats:bold>SDFZ\u20108<\/jats:bold>\n                    as a highly potent HDAC1 inhibitor (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u00a0=\u00a00.4\u00a0nM).\n                    <jats:bold>SDFZ\u20108<\/jats:bold>\n                    exhibits strong antiproliferative effects by enabling histone acetylation and inducing cell apoptosis. Crucially,\n                    <jats:bold>SDFZ\u20108<\/jats:bold>\n                    treatment led to a significant enhancement of antitumor immunity, as evidenced by\u00a0increased activation of T cells, enhanced polarization of M1\u2010type macrophages, improved antigen presentation, and alleviation of the immunosuppressive tumor microenvironment. Specifically, we observed that\n                    <jats:bold>SDFZ\u20108<\/jats:bold>\n                    notably upregulated the expression of PD\u2010L1 in both tumor cells and tumor\u2010infiltrating lymphocytes, which is closely associated with its inhibition against HDAC1. Of particular interest, combining\n                    <jats:bold>SDFZ\u20108<\/jats:bold>\n                    with PD\u2010L1 blockade resulted in a synergistic antitumor effect surpassing that of either monotherapy. Taken together, our findings establish\n                    <jats:bold>SDFZ\u20108<\/jats:bold>\n                    as a novel HDAC1 inhibitor\u00a0that concurrently targets tumor cells and immune evasion mechanisms, providing a rational combinatorial strategy to enhance cancer immunotherapy efficacy.\n                  <\/jats:p>","DOI":"10.1002\/mco2.70500","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T06:53:05Z","timestamp":1763535185000},"source":"Crossref","is-referenced-by-count":1,"title":["Preclinical Characterization of SDFZ\u20108, a Highly Potent HDAC1 Inhibitor, for Cancer Immunotherapy"],"prefix":"10.1002","volume":"6","author":[{"given":"Yi","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds School of Pharmaceutical Science, Cheeloo College of Medicine, Shandong University  Ji'nan Shandong China"},{"name":"Department of Pharmacy Shandong Provincial Hospital Affiliated to Shandong First Medical University  Ji'nan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jintong","family":"Du","sequence":"additional","affiliation":[{"name":"Shandong Cancer Hospital and Institute Shandong First Medical University  Ji'nan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds School of Pharmaceutical Science, Cheeloo College of Medicine, Shandong University  Ji'nan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huajun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Immunopharmaceutical Sciences School of Pharmaceutical Science Cheeloo College of Medicine, Shandong University  Ji'nan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junxin","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds School of Pharmaceutical Science, Cheeloo College of Medicine, Shandong University  Ji'nan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry State Key Laboratory of Discovery and Utilization of Functional 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