Repositioning Antihistamine for Cancer Therapy: Clemizole as a Template for the Design of Liver Tissue-Targeting...

Histamine receptor H₁ (HRH1) is upregulated within the tumor microenvironment, where it supports tumorigenesis by several mechanisms. Cationic amphiphilic drugs targeting HRH1 are currently under investigation for repurposing into cancer therapy. Herein, we showed that Clemizole, a first-generation HRH1 antagonist that selectively accumulates within the liver, could be used as a template to design small-molecule epigenetic modifiers targeting histone deacetylases (HDACs) and histone lysine demethylases (KDMs). The resulting HDACi and KDMi have midnanomolar to single-digit micromolar IC₅₀s and potency enhancement of 15-105 folds relative to Clemizole. Several of these compounds elicited cancer cell line-dependent cytotoxicity. Representative lead KDMi, Cle-C6K, and Cle-C8K caused transcriptome-level perturbations favoring cell cycle inhibition and apoptosis. Moreover, Cle-C8K is nontoxic and selectively accumulated in the liver of C57BL/6 mice. Collectively, our data reveal that Clemizole could be repositioned to design liver tissue-accumulating epigenetic-modifying small molecules as potential targeted antiliver cancer agents.