Development of a benzarone derivative as targeted therapy for SHH-medulloblastoma [Day 1]

Medulloblastoma is one of the most common malignant brain tumors of children, and 30% of medulloblastomas are driven by gain-of-function genetic lesions in the Sonic hedgehog (SHH) signaling pathway. Eyes Absent (EYA1), a haloacid dehalogenase (HAD) phosphatase and co-transcription factor, is critical for tumorigenesis and proliferation of SHH-medulloblastoma (SHH-MB). Benzarone and benzbromarone have been identified as allosteric inhibitors for the Eya proteins. Using benzarone as a point of departure, we developed a panel of 35 derivatives, and identified one new compound, DS-1-38, that functions as an Eya-antagonist, opposes SHH-signaling, inhibits SHH-MB growth in vitro and in vivo, shows excellent brain penetrance and increases the lifespan of mice predisposed to fatal SHH-MB. Our data suggest that DS-1-38 provides a path for developing targeted therapeutic for pediatric SHH-MB. Overall design: Comparative analysis of MB21 cells after 5 days of treatment with a benzarone derivative, DS-1-38, and vehicle, DMSO

髓母细胞瘤（Medulloblastoma）是儿童最常见的恶性脑肿瘤之一，其中30%的髓母细胞瘤由音猬因子（Sonic hedgehog, SHH）信号通路的功能获得性遗传损伤驱动。眼睛缺失蛋白1（Eyes Absent, EYA1）作为一种卤酸脱卤酶（haloacid dehalogenase, HAD）磷酸酶兼共转录因子，对SHH型髓母细胞瘤（SHH-MB）的肿瘤发生与细胞增殖至关重要。苯扎隆（Benzarone）与苯溴马隆（benzbromarone）已被证实为Eya蛋白的变构抑制剂。本研究以苯扎隆为起点，构建了包含35种衍生物的化合物库，并筛选得到新型化合物DS-1-38：该化合物可作为Eya蛋白拮抗剂，阻断SHH信号通路，在体外与体内均可抑制SHH-MB的生长，展现出优异的脑穿透性，还能延长易患致死性SHH-MB小鼠的生存期。本研究数据表明，DS-1-38为儿童SHH型髓母细胞瘤的靶向治疗药物开发提供了可行路径。实验整体设计：对经苯扎隆衍生物DS-1-38与溶剂二甲基亚砜（DMSO）处理5天的MB21细胞开展对比分析。