Nur77, an orphan nuclear receptor, is a member of the nuclear receptor superfamily. Nur77 plays important roles in various biological processes. Previously we reported that BI1071(DIM-C-pPhCF₃⁺MeSO₃^-), an oxidized form and methanesulfonate salt of (4-CF₃-Ph-C-DIM), can modulate Nur77’s non-genomic apoptotic pathway through that Nur77 translocated from the nucleus to mitochondria to induce cytochrome c releasing and promote apoptosis of cancer cell. Here we report our efforts to further optimize BI1071. A series of BI1071 analogues were designed, synthesized and their apoptosis potency was systematically evaluated. Our preliminary structure-activity relationship study identified compound 10b as a better modulator with strong binding to Nur77 and enhanced apoptotic activity. Binding studies demonstrated that 10b could bind to its target Nur77 with an affinity value of 33 nM. Furthermore, mechanism studies reveal that 10b acts as an anticancer agent by utilizing the Nur77-Bcl-2 apoptotic pathway.

Nur77是一种孤儿核受体，是核受体超家族的成员。Nur77在各种生物过程中起着重要作用。先前我们曾报道过，BI1071（DIM-C-pPhCF ₃ ⁺ MeSO ₃ ^-），（4-CF ₃ -Ph-C-DIM）的氧化形式和甲磺酸盐可以通过Nur77易位来调节Nur77的非基因组凋亡途径。从细胞核到线粒体诱导细胞色素c释放并促进癌细胞凋亡。在这里，我们报告了我们为进一步优化BI1071所做的努力。设计，合成了一系列的BI1071类似物，并系统地评估了它们的凋亡潜能。我们初步的构效关系研究确定了化合物10b作为与Nur77的强结合和增强的凋亡活性的更好的调节剂。结合研究表明10b可以以33 nM的亲和力结合其靶标Nur77。此外，机理研究表明10b通过利用Nur77-Bcl-2凋亡途径充当抗癌剂。