Estrogen receptor is a nuclear receptor activated by estrogen, existing inside cells. The receptor contains two types, ERα and ERβ. The former is always expressed in breast cancer, which causes great death among women around the world. Consequently, trying to find a potent ERα inhibitor is a possible way to prevent breast cancer.

Recently, a report by Xiaoling Puyang, et al., introduced the discovery of the potent antagonist. H3B-5942, a small compound, occurred in the process. H3B-5942 is a selective and irreversible estrogen receptor covalent antagonist, inactivates both ERαWT and ERα mutation. The Ki values are 1 nM and 0.41 nM, respectively.

To begin with, they proved H3B-5942 to specifically engage covalently with C530 of ERα via intact mass spectrometry. The binding enforces antagonist conformation different from SERMs (selective ER modulators)/SERDs (selective ER downregulators).

Next, they studied the anti-tumor activity of H3B-5942 in cells. H3B-5942 potently inhibits the proliferation of MCF7-Parental, MCF7-LTED-ERαWT, and MCF7-LTED-ERαY537C lines in deed. Besides, H3B-5942 combined with CDK4/6 inhibitors enhances the effect on cancer cells. The combination is more effective than H3B-5942 alone.

Finally, H3B-5942 is assayed in vivo. They chose the athymic female nude mice bearing cancer cells as research object. Consistent with the in vitro results, H3B-5942 suppresses tumor growth in a dose-dependent manner both in MCF7 xenograft model and in ERαY537S/WT ST941 model.

In a word, as a potent ERα inhibitor, H3B-5942 is identified as a potent and selective estrogen receptor covalent antagonist (SERCA). It targets ERα, inhibits ERα-dependent transcription, and has potential for cancer treatment in the future.