Design, synthesis and structure-activity relationship study of novel indole-pyrrole scaffold compounds targeting Nur77 in colorectal tumor cells

Nur77, an Orphan Nuclear Receptor, is involved in the development and progression of multiple tumors. In our previous study, we have shown that the protein level of Nur77 is elevated in colon tumors compared to adjacent normal tissues, highlighting its potential as a promising target for colorectal Cancer therapy. Significantly, we have identified BI1071 as a Nur77-targeting compound that induces Apoptosis in colorectal Cancer cells. Based on the scaffold of BI1071, by substituting the indole group of BI1071 with a pyrrolyl group on one side, we rationally designed and synthesized a series of novel BI1071 analogues named SIM-C-PhCF₃⁺Cl^- targeting Nur77, and the structure-activity relationship of these BI1071 derivatives was summarized. From this series of compounds, A6 exhibited the strongest binding affinity to Nur77 (K_d = 0.40 ± 0.05 μM) and the most potent anti-proliferative activity against HCT116 and MC38 colorectal tumor cell lines, with IC₅₀ values of 0.53 ± 0.06 μM and 0.16 ± 0.007 μM, respectively. Interestingly, unlike BI1071, which triggers Nur77-dependent Apoptosis, compound A6 suppressed colon Cancer cell proliferation predominantly by inducing Nur77-dependent mitotic arrest. Collectively, our findings provide a foundation for further investigation and development of Nur77-targeting antimitotic molecules toward colorectal Cancer therapy.

BI1071 analogues; Colorectal cancer; Mitotic arrest; Nur77; Rational design.