A MYC inhibitor selectively alters the MYC and MAX cistromes and modulates the epigenomic landscape to regulate target gene expression

Holmes, Austin G; Parker, J. Brandon; Sagar, Vinay; Truica, Mihai I.; Soni, Pritin N.; Han, Huiying; Schiltz, Gary E.; Abdulkadir, Sarki A.; Chakravarti, Debabrata

doi:10.1126/sciadv.abh3635

Cited by 25 publications

(19 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There was no impact on the expression of other MYC non-ribosomal target genes (MCM4, MCM10, Cdc20, and AURKB. Table S2), − the ones not bound and regulated directly by WDR5 or MLL-targeted HoxAs genes, which are consistent with the selectivity finding in the target engagement assays (Figure S3).…”

Section: Resultssupporting

confidence: 84%

Discovery and Structure-Based Design of Inhibitors of the WD Repeat-Containing Protein 5 (WDR5)–MYC Interaction

et al. 2023

View full text Add to dashboard Cite

WDR5 is a critical chromatin cofactor of MYC. WDR5 interacts with MYC through the WBM pocket and is hypothesized to anchor MYC to chromatin through its WIN site. Blocking the interaction of WDR5 and MYC impairs the recruitment of MYC to its target genes and disrupts the oncogenic function of MYC in cancer development, thus providing a promising strategy for the treatment of MYC-dysregulated cancers. Here, we describe the discovery of novel WDR5 WBM pocket antagonists containing a 1-phenyl dihydropyridazinone 3-carboxamide core that was identified from high-throughput screening and subsequent structure-based design. The leading compounds showed sub-micromolar inhibition in the biochemical assay. Among them, compound 12 can disrupt WDR5–MYC interaction in cells and reduce MYC target gene expression. Our work provides useful probes to study WDR5–MYC interaction and its function in cancers, which can also be used as the starting point for further optimization toward drug-like small molecules.

show abstract

Section: Resultssupporting

confidence: 84%

Discovery and Structure-Based Design of Inhibitors of the WD Repeat-Containing Protein 5 (WDR5)–MYC Interaction

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Because of the broad regulation of cancer hallmarks by EBTFs, there's a higher chance that these drugs will synergize with current therapeutics to improve outcome. Successful examples include a MYC small molecule inhibitor, which is shown to synergize with anti-hormone therapy to inhibit prostate cancer and breast cancer cells (200), and several other studies that evaluated the efficacy of HIF inhibitors in combination therapies (Figure 5).…”

Section: Discussionmentioning

confidence: 99%

E-box binding transcription factors in cancer

2023

View full text Add to dashboard Cite

E-boxes are important regulatory elements in the eukaryotic genome. Transcription factors can bind to E-boxes through their basic helix-loop-helix or zinc finger domain to regulate gene transcription. E-box-binding transcription factors (EBTFs) are important regulators of development and essential for physiological activities of the cell. The fundamental role of EBTFs in cancer has been highlighted by studies on the canonical oncogene MYC, yet many EBTFs exhibit common features, implying the existence of shared molecular principles of how they are involved in tumorigenesis. A comprehensive analysis of TFs that share the basic function of binding to E-boxes has been lacking. Here, we review the structure of EBTFs, their common features in regulating transcription, their physiological functions, and their mutual regulation. We also discuss their converging functions in cancer biology, their potential to be targeted as a regulatory network, and recent progress in drug development targeting these factors in cancer therapy.

show abstract

“…It's worth noting that OmoMYC, being a peptide/small protein, may be susceptible to in vivo degradation. Although other small molecules like 10058‐F4, 10074‐G5, KJ‐Pyr‐9, MYCMI‐6, MYCi361 and MYCi975 also inhibit Myc–Max interaction, their activity is limited to specific cancer types and has been associated with side effects 9–14. Therefore, there is a growing demand for novel c‐Myc inhibitors capable of targeting a broader spectrum of cancers and facilitating combination therapies.…”

Section: Introductionmentioning

confidence: 99%

Development, synthesis and validation of improved c‐Myc/Max inhibitors

Yıldırım,

Kocabaş,

Mermer

2024

J Cellular Molecular Medi

View full text Add to dashboard Cite

The pathophysiological foundations of various diseases are often subject to alteration through the utilization of small compounds, rendering them invaluable tools for the exploration and advancement of novel therapeutic strategies. Within the scope of this study, we meticulously curated a diverse library of novel small compounds meticulously designed to specifically target the c‐Myc/Max complex. We conducted in vitro examinations of novel c‐Myc inhibitors across a spectrum of cancer cell lines, including PANC1 (pancreatic adenocarcinoma), MCF7 (breast carcinoma), DU‐145 (prostate carcinoma), and A549 (lung cancer). The initial analysis involved a 25 μM dose, which enabled the identification of potent anticancer compounds effective against a variety of tumour types. We identified c‐Myc inhibitors with remarkable potency, featuring IC50 values as low as 1.6 μM and up to 40 times more effective than the reference molecule in diminishing cancer cell viability. Notably, c‐Myc‐i7 exhibited exceptional selectivity, displaying 37‐fold and 59‐fold preference for targeting prostate and breast cancers, respectively, over healthy cells. Additionally, we constructed drug‐likeness models. This study underscores the potential for in vitro investigations of various tumour types using novel c‐Myc inhibitors to yield ground‐breaking and efficacious anticancer compounds.

show abstract

A MYC inhibitor selectively alters the MYC and MAX cistromes and modulates the epigenomic landscape to regulate target gene expression

Cited by 25 publications

References 73 publications

Discovery and Structure-Based Design of Inhibitors of the WD Repeat-Containing Protein 5 (WDR5)–MYC Interaction

Discovery and Structure-Based Design of Inhibitors of the WD Repeat-Containing Protein 5 (WDR5)–MYC Interaction

E-box binding transcription factors in cancer

Development, synthesis and validation of improved c‐Myc/Max inhibitors

Contact Info

Product

Resources

About