# Identification of a novel minor-groove DNA binder that represses mitochondrial gene expression and induces apoptosis in highly aggressive leiomyosarcoma cells

## TL;DR

A new DNA-binding compound, XMH95, was found to kill aggressive leiomyosarcoma cells by boosting apoptosis-related genes and disrupting mitochondrial gene expression.

## Contribution

XMH95 is a novel minor-groove DNA binder that uniquely suppresses mitochondrial gene expression and induces apoptosis in aggressive LMS cells.

## Key findings

- XMH95 selectively induces apoptosis in aggressive LMS cells by upregulating BH3-only genes PMAP1/NOXA, BIK, HRK, and BBC3/PUMA.
- XMH95 binds DNA's minor groove and converts to a fluorescent form only after binding, unlike Hoechst 33258.
- XMH95 suppresses mitochondrial gene expression and impairs both nuclear and mitochondrial transcription to trigger apoptosis.

## Abstract

Leiomyosarcoma (LMS) is an aggressive tumor for which there are few effective therapeutic options. Through a combination of in silico and in vitro screens, we have identified the compound NSC-260594/XMH95 as a promising molecule that selectively induces apoptosis in aggressive LMS cells by upregulating the BH3-only genes PMAP1/NOXA, BIK, HRK and BBC3/PUMA. Similar to the dye Hoechst 33258, XMH95 appears to bind the minor groove of DNA. Unlike Hoechst 33258, XMH95 converts to a fluorescent form only after DNA binding. Furthermore, unlike Hoechst 33258, XMH95 suppresses mitochondrial gene expression and is a more effective inducer of apoptosis. Apart from suppressing mitochondrial genes, XMH95 has many effects on gene expression that it shares with Hoechst 33258. By inhibiting mitochondrial transcription, we show that XMH95 induces apoptosis by impairing both nuclear and mitochondrial transcription. In summary, XMH95 is a novel DNA binder that triggers apoptosis by upregulating multiple BH3-only genes.