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Subtype-selective prenylated isoflavonoids disrupt regulatory drivers of MYCN-amplified cancers

ABSTRACT: Subtype-selective prenylated isoflavonoids disrupt regulatory drivers of MYCN-amplified cancers

PROVIDER: PRJNA1026607 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26341900_1.fastq.gz	Fastqsanger.gz
	SRR26341900_2.fastq.gz	Fastqsanger.gz
	SRR26342000.fastq.gz	Fastqsanger.gz
	SRR26342100.fastq.gz	Fastqsanger.gz
	SRR26342200.fastq.gz	Fastqsanger.gz

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Subtype-selective prenylated isoflavonoids disrupt regulatory drivers of MYCN-amplified cancers

Project description:Transcription factors have proven difficult to target with small molecule inhibitors because they often lack deep pockets necessary for potent binding. Alternatively, disruption of protein expression can suppress difficult targets and enable therapeutic intervention. To this end, we have developed a drug discovery workflow that incorporates cell line-selective screening and high-throughput expression profiling followed by regulatory network analysis to identify compounds that suppress regulatory drivers of disease. Applying this approach to neuroblastoma (NBL), we screened bioactive molecules in cell lines representing the MYC-dependent (MYCNA) and mesenchymal (MES) subtypes to identify selective compounds, followed by PLATESeq profiling of treated cells. This revealed compounds that disrupt a network of MYCNA-specific regulatory proteins, resulting in MYCN degradation in vivo. The top hit was isopomiferin, a prenylated isoflavonoid that inhibited Casein Kinase 2 (CK2) in cells. Isopomiferin and its structural analogs inhibited MYC and MYCN in NBL and lung cancer cells, highlighting the general MYC-inhibiting potential of this unique scaffold.

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