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Here, we integrate theoretical simulations, sophisticated biophysical evaluations and cellular assays to characterize potent TTD binders. Screening of small drug\u2010 and fragment\u2010like collections identifies several TTD ligands, with the most promising hit being the local anesthetic hydroxyprocaine. The ligand is characterized in terms of its binding requisites by calorimetry, affording a\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>d<\/jats:sub>\n                    of 1.46\u2009\u03bcM and a well\u2010balanced thermodynamic profile. Molecular dynamics simulations combined with heat capacity measurements and osmotic stress titrations confirm that hydroxyprocaine binds stably to the TTD by displacing approximately 26 interfacial water molecules upon complexation. A targeted follow\u2010up screen focusing on sodium channel blockers yields two additional, although less promising hits, mexiletine and triamterene. In the DU145 prostate cancer cell line, hydroxyprocaine treatment significantly up\u2010regulates key downstream targets including the tumor\u2010suppressor p53 and, to a lesser degree, the stress and inflammation regulators p38 and p65, respectively, while exhibiting very low cytotoxicity. Finally, a previously undocumented interdomain interaction between TTD and its N\u2010terminal adjacent Ubiquitin\u2010like domain is reported, introducing a novel, potentially druggable UHRF1 regulatory feature. Together, these findings establish hydroxyprocaine as a highly viable chemical scaffold for TTD\u2010targeted drug development.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70473","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T02:01:06Z","timestamp":1787968866000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sodium Channel Blockers Demonstrate Binding Affinity for the Tandem Tudor Domain of the Epigenetic Hub UHRF1"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3197-1624","authenticated-orcid":false,"given":"Efstratios","family":"Tsakalidis","sequence":"first","affiliation":[{"name":"Division of Pharmaceutical Chemistry Department of Pharmacy National and Kapodistrian University of Athens  Athens 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