biostudies-literatureStokes MENCI NIH HHSNIH HHS805-819.e9https://www.ebi.ac.uk/biostudies/studies/S-EPMC11031350biostudies-literatureUnknown31(4)Transcription factors have proven difficult to target with small molecules because they lack pockets necessary for potent binding. Disruption of protein expression can suppress targets and enable therapeutic intervention. To this end, we 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 its MYC-dependent (MYCNA) and mesenchymal (MES) subtypes to identify selective compounds, followed by PLATESeq profiling of treated cells. This revealed compounds that disrupt a sub-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.Cell chemical biologySubtype-selective prenylated isoflavonoids disrupt regulatory drivers of MYCN-amplified cancers.PMC11031350R35 CA197745U54 CA209997U01 CA217858S10 OD012351R35 CA209896P01 CA087497S10 OD032433U01 CA272610S10 OD021764Small JCZask AVasciaveo ASmith NWang QCalifano AStockwell BRDaniels JRajbhandari PForouhar FReznik EStokes MEfalseSubtype-selective prenylated isoflavonoids disrupt regulatory drivers of MYCN-amplified cancers.Transcription factors have proven difficult to target with small molecules because they lack pockets necessary for potent binding. Disruption of protein expression can suppress targets and enable therapeutic intervention. To this end, we 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 its MYC-dependent (MYCNA) and mesenchymal (MES) subtypes to identify selective compounds, followed by PLATESeq profiling of treated cells. This revealed compounds that disrupt a sub-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.2024-01-01T00:00:00Z2024 Apr2026-06-01T14:54:40.585Z2026-04-08T13:28:23.667ZS-EPMC110313503806135610.1016/j.chembiol.2023.11.007