Department of Pharmaceutical Sciences, the University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Chemistry, the University of Nebraska at Omaha, 6001 Dodge Street, Omaha, NE 68182, USA.
J Control Release. 2023 Feb;354:80-90. doi: 10.1016/j.jconrel.2022.12.055. Epub 2023 Jan 5.
Medulloblastoma (MB) is a malignant pediatric brain tumor which shows upregulation of MYC and sonic hedgehog (SHH) signaling. SHH inhibitors face acquired resistance, which is a major cause of relapse. Further, direct MYC oncogene inhibition is challenging, inhibition of MYC upstream insulin-like growth factor/ phosphatidylinositol-4,5-bisphosphate 3-kinase (IGF/PI3K) is a promising alternative. While PI3K inhibition activates resistance mechanisms, simultaneous inhibition of bromodomain-containing protein 4 (BRD4) and PI3K can overcome resistance. We synthesized a new molecule 8-(2,3-dihydrobenzo[b] [1, 4] dioxin-6-yl)-2-morpholino-4H-chromen-4-one (MDP5) that targets both BRD4 and PI3K pathways. We used X-ray crystal structures and a molecular modeling approach to confirm the interactions between MDP5 with bromo domains (BDs) from both BRD2 and BRD4, and molecular modeling for PI3K binding. MDP5 was shown to inhibit target pathways and MB cell growth in vitro and in vivo. MDP5 showed higher potency in DAOY cells (IC 5.5 μM) compared to SF2523 (IC 12.6 μM), and its IC values in HD-MB03 cells were like SF2523. Treatment of MB cells with MDP5 significantly decreased colony formation, increased apoptosis, and halted cell cycle progression. Further, MDP5 was well tolerated in NSG mice bearing either xenograft or orthotopic MB tumors at the dose of 20 mg/kg, and significantly reduced tumor growth and prolonged animal survival.
髓母细胞瘤（MB）是一种恶性小儿脑肿瘤，表现出 MYC 和 sonic hedgehog（SHH）信号通路的上调。SHH 抑制剂面临获得性耐药，这是复发的主要原因。此外，直接抑制 MYC 癌基因具有挑战性，抑制 MYC 上游胰岛素样生长因子/磷脂酰肌醇-4,5-二磷酸 3-激酶（IGF/PI3K）是一种很有前途的替代方法。虽然 PI3K 抑制会激活耐药机制，但同时抑制溴结构域蛋白 4（BRD4）和 PI3K 可以克服耐药性。我们合成了一种新的分子 8-(2,3-二氢苯并[b] [1,4]二恶英-6-基)-2-吗啉-4H-色烯-4-酮（MDP5），该分子同时靶向 BRD4 和 PI3K 途径。我们使用 X 射线晶体结构和分子建模方法来确认 MDP5 与 BRD2 和 BRD4 的溴结构域（BD）之间的相互作用，以及与 PI3K 的结合的分子建模。MDP5 在体外和体内均能抑制靶标途径和 MB 细胞的生长。与 SF2523（IC 12.6 μM）相比，MDP5 在 DAOY 细胞中的效力更高（IC 5.5 μM），而在 HD-MB03 细胞中的 IC 值与 SF2523 相似。用 MDP5 处理 MB 细胞可显著降低集落形成，增加细胞凋亡，并阻止细胞周期进程。此外，在以 20 mg/kg 剂量携带异种移植或原位 MB 肿瘤的 NSG 小鼠中，MDP5 耐受性良好，显著减少肿瘤生长并延长动物存活时间。
