Abstract P2-09-06: The structure design and biological activities of inhibitory peptides, which block the interactions among polycomb repressive complex 2

Abstract

Abstract Polycomb repressive complex (PRC2) contains several proteins, including embryonic ectoderm development (EED), suppressor of zeste 12 (SUZ12) and enhancer of zeste homolog 2 (EZH2). Excessive EZH2 concentrations have been reported as a marker of aggressive breast cancer and associated with invasion and cancer progression. EZH2 levels were elevated in patients with invasive breast carcinoma relative to normal or atypical hyperplasia. Except for the C-terminal SET domain, which functions as a histone-lysine N-methyltransferases, EZH2 has an N-terminal alpha helix region, which forms tight complex with EED protein. The in vivo enzymatic activity of EZH2 relies on and be tightly regulated by the interaction with EED. We designed series of artificial peptides trying to block the interaction between EZH2 and EED. By using label-free surface plasmon resonance (SPR) technology, the dynamic binding capacities of these peptides were tested. There were 3 leading structures standing out from the screening of more 80 peptides. After several round of co-crystal structure based optimization, the binding capacity of one inhibitor was reached to several nM levels, which indicated the availability for being a drug candidate. Finally, the biological activities of the inhibitory peptides were tested in several breast cancer cell lines. The PRC2 inhibitory peptides in this study are the first time reported PRC2 targeting epigenetic molecules with biological activity in breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-09-06.