# Repositioning Antihistamine for Cancer Therapy: Clemizole as a Template for the Design of Liver Tissue-Targeting Epigenetic-Modifying Agents

## TL;DR

This paper explores using Clemizole, an antihistamine, as a template to design liver-targeting drugs that modify epigenetics for cancer therapy.

## Contribution

The study introduces a novel approach to reposition Clemizole for liver-targeted epigenetic cancer therapy.

## Key findings

- Clemizole-derived compounds show enhanced potency against HDACs and KDMs compared to Clemizole.
- Lead compounds Cle-C6K and Cle-C8K induce cell cycle inhibition and apoptosis in cancer cells.
- Cle-C8K is nontoxic and selectively accumulates in the liver of mice.

## Abstract

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.