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.

事实证明，转录因子很难用小分子靶向，因为它们缺乏有效结合所需的口袋。蛋白质表达的破坏可以抑制靶标并实现治疗干预。为此，我们开发了一种药物发现工作流程，其中包括细胞系选择性筛选和高通量表达谱分析，然后进行调控网络分析，以识别抑制疾病调控驱动因素的化合物。将这种方法应用于神经母细胞瘤 (NBL)，我们筛选了代表其 MYC 依赖性 (MYCNA) 和间充质 (MES) 亚型的细胞系中的生物活性分子，以鉴定选择性化合物，然后对处理的细胞进行 PLATESeq 分析。这揭示了破坏 MYCNA 特异性调节蛋白子网络的化合物，导致 MYCN在体内降解。最受欢迎的是 isopomiferin，一种异戊二烯化异黄酮类化合物，可抑制细胞中的酪蛋白激酶 2 (CK2)。 Isopomiferin 及其结构类似物抑制 NBL 和肺癌细胞中的 MYC 和 MYCN，凸显了这种独特支架的一般 MYC 抑制潜力。