Identification of a cytisine-based EED-EZH2 protein-protein interaction inhibitor preventing metastasis in triple-negative breast cancer cells

Abstract

Enhancer of zeste homolog 2 (EZH2) is activated in breast cancer, particularly in triple-negative breast cancer (TNBC), and is critical for cell invasion. It interacts with embryonic ectoderm development (EED) in maintaining cancer stem cells (CSC) and epithelial-mesenchymal transition (EMT) properties, hence promoting CSC metastasis. Because the association of EZH2 with EED promotes the catalytic activity of EZH2, inhibiting the EED-EZH2 interaction is a potential therapeutic strategy for treating EZH2-dependent cancer. Although several EED-EZH2 protein-protein interaction (PPI) inhibitors have been developed, few target EED. Here, we identified that a cytisine derivative compound (1) potently binds EED, thus blocking the EED-EZH2 PPI. Compound 1 was found to inhibit cell proliferation and suppress the growth of 3D tumor spheres of TNBC cells. Moreover, by reversing EMT and decreasing the ratio of CSCs, the compound inhibited TNBC metastasis and invasion ability. Therefore, targeting EED to disrupt the EED-EZH2 PPI may provide a new approach for treating TNBC metastasis. To our knowledge, compound 1 is the first cytisine-based EED-EZH2 PPI inhibitor preventing metastasis in TNBC cells. This study may provide a new avenue for the development of more efficacious EED-EZH2 PPI inhibitors in TNBC treatment.

Arf6 as a therapeutic target: Structure, mechanism, and inhibitors

“…Malignant tumor cells acquire abnormal movement to intrude into the surrounding tissue parenchyma 46 . Polarized cellular response allows cancer cells to move forward and up the chemoattractant gradient, which is an effective motility of multiple tumor cells 47 , 48 . Arf6 regulates polarized morphology, endocytic trafficking and actin remodeling of cells.…”

A state-of-the-art review on LSD1 and its inhibitors in breast cancer: Molecular mechanisms and therapeutic significance

“…Natural products are one of the major sources in drug discovery due to their diverse chemical scaffolds and activity profiles (Fang et al, 2020;Yang et al, 2020;Yang et al, 2021a;Cheng et al, 2022b;Song et al, 2022). Many natural products and their derivatives have been found with in vitro inhibitory activity against LSD1.…”

“…Targeting the protein-protein interaction (PPI) is also an effective method to improve the selectivity of enzymes (Yang et al, 2018a;Cheng et al, 2020;Yang et al, 2021a;Yang et al, 2021c;Yang et al, 2021d;Yang et al, 2022), blocking the interaction between LSD1 and its client proteins may be also a useful strategy to develop selective LSD1 inhibitors. Metal complexes have showed promising in vivo activity for BC treatment (Yang et al, 2018b;Cheng et al, 2022b), andYang et al (2017) have also identified a rhodiumbased LSD1 inhibitor with in cellulo anticancer activity against prostate cancer, which suggested this kind of compound is a unique source for the discovery of potent and selective LSD1 inhibitors against BC treatment. Several drug design strategy such as computer aided drug optimization and proteolysis targeting chimera (PROTAC)-strategy have been introduced to discover lead compounds against LSD1 with better biocompatibility and in vivo potency (Liu et al, 2020b;Martín-Acosta and Xiao, 2021).…”

Computational strategies for PROTAC drug discovery

“…Molecular docking has been one of the most commonly used types of structure-based drug design since the development of the first algorithms in the 1980s. Our group has discovered several protein-protein interaction inhibitors through in silico virtual screening, including CDK9-cyclin T1 protein-protein interaction inhibitors [20,21], EED-EZH2 protein-protein interaction inhibitors [22], and Keap1-Nrf2 protein-protein interaction inhibitors [23].…”