Dual-acting Estrogen Receptor Modulator-Histone Lysine Demethylase Inhibitors

Epigenetic dysfunction and the malfunction of endocrine proteins such as estrogen receptor alpha (ERα) are two key mechanisms for the sustenance of breast carcinoma. Agents that target ER signaling malfunctions are standard therapies for ERα-dependent breast cancer (BCa) subtypes. Small molecule inhibitors of epigenetic modifiers, histone lysine demethylases (KDMs), have shown promise as therapeutic agents for several BCa subtypes. We demonstrated herein that the integration of ERα antagonist (Tamoxifen) and agonist (17α-ethinylestradiol) ligands with deferiprone (DFP)-derived KDM inhibitor moiety furnished dual-acting agents Tam-KDMi and EED-KDMi, respectively. These agents showed robust on-target effects and potent BCa cells-selective anti-proliferative activities. The Tam-KDMi are cytotoxic to both ERα(+) and ERα(-) BCa cells, while the lack of ER-signaling inhibition conferred an enhanced ERα(-) cells cytotoxic to the EED-KDMi. Representative lead compounds Tam-KDMi DW-116 and EED-KDMi DW-088 and DW-95 significantly reduce tumor growth in murine xenograft models of ERα(−) and ERα(+) BCas with TGI as high as 70%. Collectively, our data showed that DW-116 , DW-088 and DW-95 have a high potential as leads for the development of new agents for the treatment of BCa subtypes regardless of the tumor ER expression status.