2. Academic Validation
  3. Discovery of novel JQ1 derivatives as dual ferroptosis and apoptosis inducers for the treatment of triple-negative breast cancer

Discovery of novel JQ1 derivatives as dual ferroptosis and apoptosis inducers for the treatment of triple-negative breast cancer

  • Eur J Med Chem. 2025 Mar 15:286:117275. doi: 10.1016/j.ejmech.2025.117275.
Ran Ding 1,  Lijie Tang 1,  Dexin Zeng 2,  Jian Li 1,  Yingdong Jia 1,  Xiqing Yan 3,  Chong Zhang 4,  Liqiang Wu 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, China.
  • 2 School of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, China; Quanzhou Hospital of Traditional Chinese Medicine, Quanzhou, 362000, China.
  • 3 School of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, China. Electronic address: yxqdoctor@163.com.
  • 4 School of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, China. Electronic address: chongzhang@xxmu.edu.cn.
  • 5 School of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, China. Electronic address: wliq1974@163.com.
PMID: 39826487 DOI: 10.1016/j.ejmech.2025.117275
Abstract

The activation of Ferroptosis in refractory cancers may enhances their sensitivity to apoptosis-based chemotherapy, resulting in a synergistic effect via combination therapy. To enhance the Anticancer effect of JQ1, a known BRD4 Inhibitor with a significant antiproliferative effect on triple-negative breast Cancer (TNBC), various new JQ1 derivatives as dual Ferroptosis and Apoptosis inducers were designed and synthesized. Among them, compound BG11 revealed a remarkable inhibitory activity against TNBC cells and obviously suppressed BRD4 and GPX4 expression and activities. Further studies suggested that BG11 induced cell Ferroptosis through promoting Fe2+ and intracellular lipid peroxide deposition. In addition, BG11 could induce Apoptosis through increasing Bax (apoptotic protein) expression and decreasing Bcl-2 (anti-apoptotic protein) expression within MDA-MB-231 cells. Surprisingly, BG11 significantly inhibited tumor proliferation in the MDA-MB-231 xenograft model without obvious toxicity. Based on the above findings, BG11 may be the candidate dual Ferroptosis and Apoptosis inducers for treating TNBC.

Keywords

Apoptosis; BRD4; Ferroptosis; GPX4; TNBC.

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