Bexarotene 是一种被批准用于治疗皮肤 T 细胞淋巴瘤 (CTCL) 的药物，由于其能够作为高度特异性的视黄醇 X 受体 (RXR) 激动剂而被归类为类维生素 A。 Rexinoids 能够诱导 RXR 同二聚化，从而诱导人类癌症细胞凋亡并抑制增殖。大量研究表明，贝沙罗汀可有效降低 CTCL 细胞系的活力和增殖。然而，许多接受治疗的患者由于分别与视黄酸受体 (RAR)、甲状腺激素受体 (TR) 和肝 X 受体 (LXR) 信号传导交叉活动而出现皮肤毒性、甲状腺功能减退和高脂血症。在这项研究中，对 10 种新型类似物和三种标准化合物与贝沙罗汀驱动 RXR 同二聚化以及随后与 RXR 响应元件 (RXRE) 结合的能力进行了评估。此外，还评估了这些类似物对 CTCL 细胞的增殖抑制、细胞毒性和致突变性。此外，通过 qPCR 分析了最有效的类似物，以确定调节两个关键肿瘤抑制基因 ATF3 和 EGR3 表达的功效。我们的结果表明，这些新化合物可能具有相似或增强的治疗潜力，因为它们表现出增强的 RXR 激活，同时同等或更大程度地减少 CTCL 细胞增殖，以及诱导 ATF3 和 EGR3 的能力。这项工作拓宽了我们对 RXR-配体关系的理解，并允许开发可能更有效的药物。与母体化合物相比，RXR 激动剂的修饰可以产生具有增强的生物选择性和效力的药物，从而可能改善患者的治疗结果。

Bexarotene, a drug approved for treatment of cutaneous T-cell lymphoma (CTCL), is classified as a rexinoid by its ability to act as a retinoid X receptor (RXR) agonist with high specificity. Rexinoids are capable of inducing RXR homodimerization leading to the induction of apoptosis and inhibition of proliferation in human cancers. Numerous studies have shown that bexarotene is effective in reducing viability and proliferation in CTCL cell lines. However, many treated patients present with cutaneous toxicity, hypothyroidism, and hyperlipidemia due to crossover activity with retinoic acid receptor (RAR), thyroid hormone receptor (TR), and liver X receptor (LXR) signaling, respectively. In this study, 10 novel analogs and three standard compounds were evaluated side-by-side with bexarotene for their ability to drive RXR homodimerization and subsequent binding to the RXR response element (RXRE). In addition, these analogs were assessed for proliferation inhibition of CTCL cells, cytotoxicity, and mutagenicity. Furthermore, the most effective analogs were analyzed via qPCR to determine efficacy in modulating expression of two critical tumor suppressor genes, ATF3 and EGR3. Our results suggest that these new compounds may possess similar or enhanced therapeutic potential since they display enhanced RXR activation with equivalent or greater reduction in CTCL cell proliferation, as well as the ability to induce ATF3 and EGR3. This work broadens our understanding of RXR-ligand relationships and permits development of possibly more efficacious pharmaceutical drugs. Modifications of RXR agonists can yield agents with enhanced biological selectivity and potency when compared to the parent compound, potentially leading to improved patient outcomes.