Design, Synthesis, and Characterization of Globular Orphan Nuclear Receptor Regulator with Biological Activity in Soft Tissue Sarcoma

Sarcomas are rare and heterogeneous cancer variants of mesenchymal origin. Their genetic heterogeneity coupled with uncertain histogenesis makes them difficult to treat and results in poor prognosis. In this work, we show that structure-based drug discovery involving computational modeling can be used to identify a new retinoid X receptor (RXR) agonist ligand with a bis­(indolyl)­methane scaffold. This agent co-self-assembles with an amphiphilic diblock copolymer resulting in nanoparticles (Nano-RXR) with excellent kinetic stability, which were evaluated for efficacy and safety in transformed sarcoma cells, 63-3 Cre and 141-10 Cre of pig origin, and in rodent xenograft models. Responses at gene and protein levels established the treatment approach as a highly effective RXR agonist across cell, rodent, and “Oncopig” models. Interestingly, Nano-RXR was not only able to modulate metabolic and transporter genes related to orphan nuclear receptors but also played a major role in modulating programmed cell death in sarcomas developed in Oncopigs.肉瘤是一类起源于间叶组织的罕见且异质性显著的恶性肿瘤亚型。其遗传异质性与尚未明确的组织发生机制，导致其治疗难度极高且预后不良。本研究证实，结合计算建模的基于结构的药物发现策略，可筛选得到一种全新的、带有双吲哚甲烷骨架的维甲酸X受体（retinoid X receptor, RXR）激动剂配体。该配体可与两亲性二嵌段共聚物共同自组装，形成具备优异动力学稳定性的纳米颗粒（Nano-RXR）；研究团队随后分别在猪来源的转化肉瘤细胞系63-3 Cre与141-10 Cre，以及啮齿类动物异种移植模型中，评估了该纳米颗粒的疗效与安全性。基因与蛋白水平的应答结果证实，该治疗方案作为高效的RXR激动剂，在细胞模型、啮齿类动物模型及‘Oncopig’模型中均展现出卓越的抗肿瘤活性。值得注意的是，Nano-RXR不仅可调控与孤儿核受体相关的代谢基因与转运蛋白基因，还在调控‘Oncopig’模型中肉瘤的程序性细胞死亡过程中发挥了关键作用。