Simultaneous inhibition of multiple molecular targets is an established strategy to improve the continuance of clinical response to therapy. Here, we screened 49 molecules with dual nanomolar inhibitory activity against BRD4 and PLK1, best classified as dual kinase-bromodomain inhibitors, in pediatric tumor cell lines for their antitumor activity. We identified two candidate dual kinase-bromodomain inhibitors with strong and tumor-specific activity against neuroblastoma, medulloblastoma, and rhabdomyosarcoma tumor cells. Dual PLK1 and BRD4 inhibitor treatment suppressed proliferation and induced apoptosis in pediatric tumor cell lines at low nanomolar concentrations. This was associated with reduced MYCN-driven gene expression as assessed by RNA sequencing. Treatment of patient-derived xenografts with dual inhibitor UMB103 led to significant tumor regression. We demonstrate that concurrent inhibition of two central regulators of MYC protein family of protooncogenes, BRD4, and PLK1, with single small molecules has strong and specific antitumor effects in preclinical pediatric cancer models.

同时抑制多个分子靶点是提高临床对治疗反应持续性的既定策略。在这里，我们在儿科肿瘤细胞系中筛选了49种对BRD4和PLK1具有双重纳摩尔抑制活性的分子，这些分子最好归类为双重激酶-溴结构域抑制剂，因为它们具有抗肿瘤活性。我们确定了两个候选双激酶-bromodomain抑制剂具有强大的和针对神经母细胞瘤，髓母细胞瘤和横纹肌肉瘤细胞的肿瘤特异性活性。在低纳摩尔浓度下，PLK1和BRD4双重抑制剂治疗抑制了小儿肿瘤细胞系的增殖并诱导了细胞凋亡。这与MYCN减少有关RNA测序评估基因驱动的基因表达。用双重抑制剂UMB103治疗源自患者的异种移植物可导致显着的肿瘤消退。我们证明，同时抑制单个原小分子MYC蛋白家族的原癌基因BRD4和PLK1的两个中央调节器在临床前儿科癌症模型中具有强大而特异性的抗肿瘤作用。