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

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.