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Graphical abstract Highlights • A class of PRMT5 inhibitors with the IC 50 values ranging from 0.77 to 23 μM were identified. • The structure-activity relationship (SAR) of this class of structures was discussed. • The top two active hits (5 and 19) showed potent anti-proliferative activity against MV4-11 cells. • 5 and 19 demonstrated the mechanism of cell killing in cell cycle arrest and apoptotic effect. Abstract Protein arginine methyltransferase 5 (PRMT5) is an epigenetics related enzyme that has been validated as an important therapeutic target for glioblastoma and mantel cell lymphoma. In the present study, 11 novel PRMT5 inhibitors with 5-benzylidene-2-phenylthiazolone scaffold were identified by molecular docking-based virtual screening and structural optimization. Their IC 50 values against PRMT5 at enzymatic level were ranging from 0.77 to 23 μM. As expected, the top two active hits (5 and 19) showed potent anti-proliferative activity against MV4-11 cells with EC 50 values lower than 10 μM and reduced the cellular symmetric arginine dimethylation levels of SmD3 protein. Besides, 5 and 19 demonstrated the mechanism of cell killing in cell cycle arrest and apoptotic effect. The probable binding modes of the two compounds were explored and further verified by molecular dynamics simulation. The structure-activity relationship (SAR) of this class of structures was also discussed and further demonstrated by molecular docking simulation. [ABSTRACT FROM AUTHOR]

Polycomb repressive complex 2 (PRC2) acts as a primary writer for di- and tri-methylation of histone H3 at lysine 27. This protein plays an essential role in silencing gene expression. Enhancer of zeste 2 (EZH2), the catalytic subunit of PRC2, is considered as a promising therapeutic target for cancer. GSK126, a specific inhibitor of EZH2, is undergoing phase I trials for hypermethylation-related cancers. In addition, many derivatives of GSK126 are also commonly used in laboratory investigations. However, studies on the mechanism and drug development of EZH2 are limited by the absence of structural diversity of these inhibitors because they share similar SAM-like scaffolds. In this study, we generated a pharmacophore model based on reported EZH2 inhibitors and performed in silico screenings. Experimental validations led to the identification of two novel EZH2 inhibitors, DCE_42 and DCE_254, with IC 50 values of 23 and 11 μM, respectively. They also displayed significant anti-proliferation activity against lymphoma cell lines. Thus, we discovered potent EZH2 inhibitors with novel scaffold using combined in silico screening and experimental study. Results from this study can also guide further development of novel specific EZH2 inhibitors. [ABSTRACT FROM AUTHOR]

PolycombRepressive Complex 2 (PRC2) modulates the chromatin structureand transcriptional repression by trimethylation lysine 27 of histoneH3 (H3K27me3), a process that necessitates the protein–proteininteraction (PPI) between the catalytic subunit EZH2 and EED. DeregulatedPRC2 is intimately involved in tumorigenesis and progression, makingit an invaluable target for epigenetic cancer therapy. However, untilnow, there have been no reported small molecule compounds targetingthe EZH2-EED interactions. In the present study, we identified astemizole,an FDA-approved drug, as a small molecule inhibitor of the EZH2-EEDinteraction of PRC2. The disruption of the EZH2-EED interaction byastemizole destabilizes the PRC2 complex and inhibits its methyltransferaseactivity in cancer cells. Multiple lines of evidence have demonstratedthat astemizole arrests the proliferation of PRC2-driven lymphomasprimarily by disabling the PRC2 complex. Our findings demonstratethe chemical tractability of the difficult PPI target by a small moleculecompound, highlighting the therapeutic promise for PRC2-driven humancancers via targeted destruction of the EZH2-EED complex. [ABSTRACT FROM AUTHOR]