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

• Published in: Cell chemical biology Vol. 31; no. 4; pp. 805 - 819.e9
• Main Authors: Stokes, Michael E., Vasciaveo, Alessandro, Small, Jonnell Candice, Zask, Arie, Reznik, Eduard, Smith, Nailah, Wang, Qian, Daniels, Jacob, Forouhar, Farhad, Rajbhandari, Presha, Califano, Andrea, Stockwell, Brent R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 18.04.2024
• Subjects: casein kinase 2; Cell Line, Tumor; CK2; drug discovery; Gene Expression Regulation, Neoplastic; Humans; isoflavonoid; isopomiferin; MYCN; N-Myc Proto-Oncogene Protein - genetics; N-Myc Proto-Oncogene Protein - metabolism; neuroblastoma; Neuroblastoma - drug therapy; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; PLATESeq; pomiferin; Transcription Factors - metabolism; VIPER; MYCN; drug discovery; VIPER; isoflavonoid; neuroblastoma; pomiferin; CK2; PLATESeq; casein kinase 2; isopomiferin
• ISSN: 2451-9456; 2451-9448; 2451-9456
• DOI: 10.1016/j.chembiol.2023.11.007

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. [Display omitted] •OncoTreat prioritized subtype-selective compounds that disrupt a regulatory module•Top hits included prenylated isoflavonoid molecules that suppress MYCN protein•Pomiferin suppressed MYCN in vivo, slowing growth of SK-N-Be2 NBL xenografts•VIKING algorithm identified putative targets, including casein kinase2 (CK2) Stokes and Vasciaveo et al. evaluated selective agents targeting MYCN-amplified neuroblastoma cells using PLATE-Seq and regulatory network analysis. This revealed prenylated isoflavonoids that suppress a tumor checkpoint module, causing MYCN depletion and cell death. This paper highlights a multifaceted approach that enables screening for agents targeting networked drivers of disease.