2. Academic Validation
  3. Identification of a novel minor-groove DNA binder that represses mitochondrial gene expression and induces apoptosis in highly aggressive leiomyosarcoma cells

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

  • Cell Death Discov. 2025 Nov 10;11(1):524. doi: 10.1038/s41420-025-02803-3.
Eleonora Malavasi 1,  Raffaella Picco 1,  Showmeya Mallavarapu 1,  Martina Minisini 1,  Francesca D'Este 1,  Alessio Bertozzo 1,  Lidia Giuliani 2,  Roberta Astolfi 2,  Monica Chinellato 3,  Giacomo Bettin 1 4,  Marco Bortoluzzi 4,  Rino Ragno 2,  Alessandro Angelini 4 5,  Claudio Brancolini 6
Affiliations

Affiliations

  • 1 Department of Medicine, Lab of Epigenomics, Università degli Studi di Udine, Udine, 33100, Italy.
  • 2 Rome Center for Molecular Design, Department of Drug Chemistry and Technology, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy.
  • 3 Department of Biology, University of Padua, Via U. Bassi 58, 35131, Padova, Italy.
  • 4 Department of Molecular Sciences and Nanosystems, Ca' Foscari University of Venice, Via Torino 155, 30172, Mestre, Italy.
  • 5 European Centre for Living Technology (ECLT), Ca' Bottacin, Dorsoduro 3911, Calle Crosera, 30123, Venice, Italy.
  • 6 Department of Medicine, Lab of Epigenomics, Università degli Studi di Udine, Udine, 33100, Italy. [email protected].
PMID: 41213941 DOI: 10.1038/s41420-025-02803-3
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.

Figures
Products