Novel hybrid conjugates with dual estrogen receptor α degradation and histone deacetylase inhibitory activities for breast cancer therapy

A series of dual-functional agents targeting both ERα degradation and histone deacetylase inhibition have been discovered. Among them, conjugate 16i exhibited excellent estrogen receptor α degradation activity, histone deacetylase inhibitory activity and synergetic antiproliferation activity against MCF-7 cell lines. [Display omitted] •Novel dual-functional agents targeting both ERα degradation and histone deacetylase inhibiton have been discovered.•These novel OBHSA-HDACi conjugates showed excellent estrogen receptor α degradation activity, histone deacetylase inhibitory activity and synergetic antiproliferation activity against MCF-7 cell lines.•These OBHSA-HDACi conjugates may provide possibilities for discovery of novel SERDs or PROTAC-like compounds for breast cancer treatment. Hormone therapy targeting estrogen receptors is widely used clinically for the treatment of breast cancer, such as tamoxifen, but most of them are partial agonists, which can cause serious side effects after long-term use. The use of selective estrogen receptor down-regulators (SERDs) may be an effective alternative to breast cancer therapy by directly degrading ERα protein to shut down ERα signaling. However, the solely clinically used SERD fulvestrant, is low orally bioavailable and requires intravenous injection, which severely limits its clinical application. On the other hand, double- or multi-target conjugates, which are able to synergize antitumor activity by different pathways, thus may enhance therapeutic effect in comparison with single targeted therapy. In this study, we designed and synthesized a series of novel dual-functional conjugates targeting both ERα degradation and histone deacetylase inhibiton by combining a privileged SERD skeleton 7-oxabicyclo[2.2.1]heptane sulfonamide (OBHSA) with a histone deacetylase inhibitor side chain. We found that substituents on both the sulfonamide nitrogen and phenyl group of OBHSA unit had significant effect on biological activities. Among them, conjugate 16i with N-methyl and naphthyl groups exhibited potent antiproliferative activity against MCF-7 cells, and excellent ERα degradation activity and HDACs inhibitory ability. A further molecular docking study indicated the interaction patterns of these conjugates with ERα, which may provide guidance to design novel SERDs or PROTAC-like SERDs for breast cancer therapy.