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Small molecule MYC Inhibitor restricts ovarian tumor growth by suppressing c-Myc mediated glycolysis

ABSTRACT: Ovarian cancer is characterized by aberrant cMYC expression and dysregulated glycolysis. cMYC overexpression is linked to poorer patient survival. Since MYC protein is not part of a receptor-ligand pair and lacks a defined binding site for small molecules, MYC inhibitors are not yet available for clinical applications. Herein, we report the discovery of GD-07 a small molecule identified through high-throughput in silico screening that binds with G-quadruplex (G4) motif in c-Myc promoter. GD-07 effectively stabilizes MYC-G4 through a combination of electrostatic and noncovalent interactions. GD-07 exhibits high cytotoxicity in ovarian cancer cells (A2780) with minimal toxicity in normal cells, providing a wide therapeutic window for targeted cancer therapy. GD-07 suppresses c-Myc expression in ovarian cancer cells, which in turn curtails glucose metabolism and glycolysis. This suppression is accompanied by the promotion of p53 and pro-apoptotic markers, indicating a potential induction of cancer cell apoptosis. Notably, GD-07 exhibit superior efficacy to carboplatin in patient-derived organoids of high-grade serous ovarian cancer (HGSOC), effectively mimicking clinical responses. GD-07 disrupts metabolic pathways and induces apoptosis by modulating key oncogenic and tumor suppressor genes. Our findings highlight GD-07 as a promising therapeutic agent that selectively targets the c-Myc G-quadruplex and disrupts bioenergetics, offering a dual mechanism of action by inhibiting proliferation and promoting apoptosis. GD-07 represents a novel approach with high translational potential for treating resistant and metastatic ovarian cancer, laying the foundation for future development of next-generation cancer therapeutics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297274 | GEO | 2026/05/15

REPOSITORIES: GEO

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Project description:DNA secondary structures are important for fundamental genome functions such as transcription and replication1. The G-quadruplex (G4) structural motif has been linked to gene regulation2,3 and genome instability4,5 and may be important to cancer development and other diseases6-8. Recently, ~700,000 discrete G4s have been observed in naked human single-stranded genomic DNA using G4-seq, a high-throughput sequencing technique that detects structural features in vitro.9 It is of vital importance to investigate G4 structures within an endogenous chromatin context, which until now remained elusive10,11. Herein, we address this via the development of G4 ChIP-seq, an antibody-based G4 chromatin immunoprecipitation and high-throughput sequencing approach. We identified ~10,000 endogenous G4 structures and show that G4s are predominantly seen in regulatory, nucleosome-depleted, chromatin regions. G4s were enriched in the promoters and 5âUTR regions of highly transcribed genes, particularly in genes related to cancer and in somatic copy number amplifications, such as MYC. Reorganization of the chromatin landscape using a histone deacetylase inhibitor, resulted in de novo G4 formation in new and more prominent regulatory, nucleosome-depleted regions associated with increased transcriptional output. Our findings suggest a striking relationship between promoter nucleosome-depleted regions, G4 formation and elevated transcriptional activity. Comparison between normal human epidermal keratinocytes and their immortalized counterparts revealed a ï¾7-fold greater G4 abundance in immortalized cells, of which 80 % were found in regulatory, nucleosome-depleted regions common to both cell types. Consequently, cells exhibiting more G4s displayed significantly increased transcriptional output and were more sensitive to growth inhibition by a small molecule G4 ligand. Overall, our results provide new mechanistic insights into where and when DNA adopts G4 structure in vivo. Our findings show for the first time that regulatory, nucleosome-depleted chromatin and transcriptional states predominantly shape the endogenous G4 DNA landscape. Two cell lines, treated with entinostat or untreated, analyzed to detect gene expression differences, presence of G-Qudruplexes and chromatin state. Each combination of conditions replicated in duplicates or triplicates.

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Small molecule MYC Inhibitor restricts ovarian tumor growth by suppressing c-Myc mediated glycolysis

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