Identification of Cyproheptadine as an Inhibitor of SET Domain Containing Lysine Methyltransferase 7/9 (Set7/9) That Regulates Estrogen-Dependent Transcription

SET domain containing lysine methyltransferase
7/9 (Set7/9), a histone lysine methyltransferase (HMT), also methylates
non-histone proteins including estrogen receptor (ER) α. ERα
methylation by Set7/9 stabilizes ERα and activates its transcriptional
activities, which are involved in the carcinogenesis of breast cancer.
We identified cyproheptadine, a clinically approved antiallergy drug,
as a Set7/9 inhibitor in a high-throughput screen using a fluorogenic
substrate-based HMT assay. Kinetic and X-ray crystallographic analyses
revealed that cyproheptadine binds in the substrate-binding pocket
of Set7/9 and inhibits its enzymatic activity by competing with the
methyl group acceptor. Treatment of human breast cancer cells (MCF7
cells) with cyproheptadine decreased the expression and transcriptional
activity of ERα, thereby inhibiting estrogen-dependent cell
growth. Our findings suggest that cyproheptadine can be repurposed
for breast cancer treatment or used as a starting point for the discovery
of an anti-hormone breast cancer drug through lead optimization.