Aromatic nitroolefin with inhibition efficacy in triple-negative breast cancer cells by dual targeting RXRα and tubulins

We previously identified that 1-(2-Nitrovinyl)naphthalene (Z-10) is a ligand of retinoid x receptor α (RXRα) with a potent anti-breast Cancer efficacy and revealed that nitro group is an essential pharmacophore in Z-10. In this study, we defined that the double bond of the nitrovinyl group is also vital for Z-10 to bind and activate RXRα. Mechanistically, the double bond has a chemical ability to mediate Z-10's covalent binding of RXRα via the Michael addition reaction with Cys432. By retaining the nitrovinyl group, a series of Z-10 analogues with different aromatic groups and different aromatic ring-positions of nitrovinyl group and alkoxy groups were designed and synthesized. We found that some analogues including compound 30 show stronger ability than Z-10 in inhibiting TNFα survival signal in MDA-MB-231 breast Cancer cells. Interestingly, these RXRα ligands also bind to tubulins likely through the similar covalent interaction and induce the degradation of tubulins and cell cycle arrest in MDA-MB-231 cells, of which 30 displays the strongest efficacy. Importantly, these analogues and TNFα exhibit synergistic effects in inducing breast Cancer cell Apoptosis, of which 30 shows greater efficacy than Z-10. Together, our study provides a theoretical basis for the RXRα and tubulin dual-targeting drug design for breast Cancer treatment.