Optimization of novel oxidative DIMs as Nur77 modulators of the Nur77-Bcl-2 apoptotic pathway

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 analogs 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.