Abstract

Protein arginine methyltransferase 5 (PRMT5) is able to regulate gene transcription by catalyzing the symmetrical dimethylation of arginine residue of histone, which plays a key role in tumorigenesis. Many efforts have been taken in discovering small-molecular inhibitors against PRMT5, but very few were reported and most of them were SAM-competitive. EPZ015666 is a recently reported PRMT5 inhibitor with a new binding site, which is different from S-adenosylmethionine (SAM)-binding pocket. This new binding site provides a new clue for the design and discovery of potent and specific PRMT5 inhibitors. In this study, the structure-based virtual screening targeting this site was firstly performed to identify potential PRMT5 inhibitors. Then, the bioactivity of the candidate compound was studied. MTT results showed that compound T1551 decreased cell viability of A549 and H460 non-small cell lung cancer cell lines. By inhibiting the methyltransferase activity of PRMT5, T1551 reduced the global level of H4R3 symmetric dimethylation (H4R3me2s). T1551 also downregulated the expression of oncogene FGFR3 and eIF4E, and disturbed the activation of related PI3K/AKT/mTOR and ERK signaling in A549 cell. Finally, we investigated the conformational spaces and identified collective motions important for description of T1551/PRMT5 complex by using molecular dynamics simulation and normal mode analysis methods. This study provides a novel non-SAM-competitive hit compound for developing small molecules targeting PRMT5 in non-small cell lung cancer.

Highlights

  • Protein arginine methyltransferases (PRMTs) are a class of enzymes that transfer a methyl group from the cofactor S-adenosylmethionine (SAM) to arginine omega nitrogen of substrate protein

  • When selecting the candidate compounds, the following criteria was considered: (1) choosing one compound at most in a group to retain structural diversity; (2) occupying the binding pocket with molecular size neither too big nor too small; (3) choosing the one with with the key residues of Protein arginine methyltransferase 5 (PRMT5) (Chan-Penebre et al, 2015). smaller molecular weight or/and lower MM/GBSA score if For instance, Phe327 forms π–π interactions with THIQ compounds are similar; (4) forming the reported interactions ring of EPZ015666; THIQ forms cation–π interactions with methyl group of SAM; EPZ015666 interacts with the backbone -NH of Phe580 and side chains of Glu444

  • To gain further insight into the molecular mechanism underlying PRMT5-dependent regulation of FGFR3, we examined whether T1551 could regulate the activation of AKT, ERK, and mTOR through inhibiting PRMT5

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Summary

Introduction

Protein arginine methyltransferases (PRMTs) are a class of enzymes that transfer a methyl group from the cofactor S-adenosylmethionine (SAM) to arginine omega nitrogen of substrate protein. Sheng and Wang (2016) pointed out that PRMT5 could regulate multiple signaling pathways to promote lung cancer cell proliferation. All of these suggest that PRMT5 is a promising therapeutic target in lung cancer. The resolved PRMT5-SAM-EPZ015666 crystal complex shows that EPZ015666 does not compete with SAM, but locates in a new pocket (different from SAM-binding site) of PRMT5. This binding site in PRMT5 provides us a new way to discovery and development of more potent and specific PRMT5 inhibitors

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