2. Academic Validation
  3. Aromatic nitroolefin with inhibition efficacy in triple-negative breast cancer cells by dual targeting RXRα and tubulins

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

  • Eur J Med Chem. 2025 May 5:289:117486. doi: 10.1016/j.ejmech.2025.117486.
Xiaofang Qu 1,  Yanxia Wang 1,  Yunqing Xu 1,  Lin Xu 1,  Xiaohong Ye 2,  Hongchen Cai 1,  Liang Bu 3,  Zhiping Zeng 4,  Hu Zhou 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, 361102, China.
  • 2 School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, 361102, China; High Throughput Drug Screening Platform, Xiamen University, Xiamen, Fujian, 361102, China.
  • 3 Department of Thoracic Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, Fujian, China. Electronic address: buliang@xmu.edu.cn.
  • 4 School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, 361102, China; High Throughput Drug Screening Platform, Xiamen University, Xiamen, Fujian, 361102, China. Electronic address: zengzhiping@xmu.edu.cn.
  • 5 School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, 361102, China; High Throughput Drug Screening Platform, Xiamen University, Xiamen, Fujian, 361102, China. Electronic address: huzhou@xmu.edu.cn.
PMID: 40090298 DOI: 10.1016/j.ejmech.2025.117486
Abstract

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.

Keywords

Aromatic nitroolefin; RXRα; TNBC; TNFα; Tubulins.

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