Conversion of a selective ERβ agonist into a potent antagonist via long-chain derivatization

Estrogen receptor β (ERβ) is overexpressed in certain cancers, including triple-negative breast cancer (TNBC), and has context-dependent roles that can promote or suppress tumor progression. To explore its therapeutic potential, we designed WC10, a novel ERβ-selective antagonist based on the agonist WAY-202196. Structural modification at the cyano group with a long alkyl chain yielded WC10, which retained ERβ binding affinity while improving subtype selectivity. Fluorescence polarization assays and cellular models confirmed WC10's selective antagonism of ERβ over ERα. Importantly, WC10 suppressed ERβ-dependent proliferation in MDA-MB-231 TNBC cells, suggesting its promise as a chemical probe and potential lead compound for ERβ-targeted therapies. • WC10 is a decyl-substituted derivative of the ERβ agonist WAY-202196. • WC10 retains high ERβ affinity and selectivity while acting as an antagonist. • Alkyl chain extension at a solvent-exposed site reverses agonist activity. • WC10 inhibits ERβ-driven proliferation of triple-negative breast cancer cells. • C10 chain length showed the strongest antagonist activity among compounds tested.