Increasing evidence shows that cancer development is highly related to the alterations in the so-called histone code signaling of epigenetic information. PRMT5 (protein arginine methyltransferase 5) is an important epigenetic enzyme in this process by carrying out symmetric dimethylation on histone proteins, especially on H4R3. The abundant epigenetic modifications brought by PRMT5 help it regulate a wide variety of biological functions. Moreover, PRMT5 is also active in post-translational modification on non-histone proteins, which is reported to be involved in tumorigenesis. Recent studies find that the viability of MTAP-deficient cancer cells is highly dependent on PRMT5. Therefore, PRMT5 plays an important role in cancerogenesis as a critical oncoprotein. The overexpression of PRMT5 in a variety of cancer cells makes it a compelling novel therapeutic target for anticancer strategies. Since there is no approved drug targeting PRMT5 so far, our goal is to develop a small molecule compound that could inhibit PRMT5 activity with high potency and selectivity. Based on the crystal structure of human PRMT5:MEP50 in complex with a SAM analog and H4 published in 2012, we have identified a novel lead compound through virtual screening. We also have optimized the lead and designed de novo molecules by MLSD (multiple ligand simultaneous docking) strategy. Those molecules were evaluated in several cancer cell lines to study their antiproliferative and apoptotic effects. Furthermore, molecular level IC50s were determined in biochemical assays. For those top hits with high inhibition activities, we performed binding analysis to investigate the direct binding interaction between the small molecule and enzyme. Exact binding mode will be determined through X-ray crystallography, which is underway.

Biochemical characterization of PRMT5 inhibition by small molecules designed via structure-based design

254th National Meeting (2017)

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