Identification of a Potent Oridonin Analogue for Treatment of Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is one of the most highly invasive and metastatic breast cancers without safe and effective therapeutic drugs. The natural product oridonin is reported to be a potential anti-TNBC agent. However, its moderate activity and complex structure hampered its clinical application. In this study, the novel oridonin analogues were first identified by removal of multiple hydroxyl groups and structural simplification of oridonin. The representative analogue <b>20</b> exhibited potent anticancer effects. Further structural modification on <b>20</b> generated the most potent derivative <b>56</b>, which possessed 120-fold more potent antiproliferative activity than oridonin in the TNBC cell line HCC1806. Importantly, compound <b>56</b> exhibited more potent anticancer activity than paclitaxel in TNBC xenograft nude mice. Moreover, <b>56</b> could attenuate the expression of MMP-2, MMP-9, p-FAK, and integrin β1 to inhibit TNBC cell metastasis. All results suggest that compound <b>56</b> may warrant further investigation as a promising candidate agent for the treatment of TNBC.